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The right ventricle under pressure;
Cellular and molecular mechanisms of right heart failure in pulmonary hypertension
Harm J. Bogaard MD, PhD1,2 HYPERLINK "mailto:hjbogaard@vcu.edu"hjbogaard@vcu.edu
Kohtaro Abe MD, PhD2,3 HYPERLINK "mailto:kabe@vcu.edu"kabe@vcu.edu2
Anton Vonk Noordegraaf, MD PhD1 HYPERLINK "mailto:a.vonk@vumc.nl"a.vonk@vumc.nl
Norbert F. Voelkel, MD2
1Dept of Pulmonary Medicine, VU University Medical Center, Amsterdam, The Netherlands; 2Dept of Pulmonary Medicine and Critical Care, Virginia Commonwealth University, Richmond, Virginia; 3Dept of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
First Author: Harm J Bogaard
Contact Address: 1101 E Marshall Street
Sanger Hall room 7-020
Richmond VA 23298
Fax: 001-804-628-0325
Tel: 001-804-628-9618
Correspondence to: Norbert Voelkel HYPERLINK "mailto:nvoelkel@mcvh-vcu.edu"nvoelkel@mcvh-vcu.edu
Conflict of interest statement: There are no conflicts of interest for any of the authors
Abbreviations
AC adenylate cyclase
ACE angiotensin converting enzyme
ADAM-12 a disintegrin and metalloprotease 12
AM adrenomedullin
ANP atrial natriuretic peptide
ATII angiotensin II
AT1R angiotensin type 1 receptor
- A R - a d r e n e r g i c r e c e p t o r
- A R K - A R k i n a s e
B N P b r a i n n a t r i u r e t i c p e p t i d e
C a M K I I C a 2 + - c a l m o d u l i n d e p e n d e n t p r o t e i n k i n a s e I I
c A M P c y c l i c a d e n o s i n e m o n o p h o s p h a t e
c G M P c y c l i c g u a n o s i n e m o n o p h o s p h a t e
C R E B c A M P - r e s p o n s e e l e m e n t b i n d i n g p r o t e i n
C S C c a r d i a c s tem cell
CT-1 cardiotropin-1
Cu copper
DAG diacylglycerol
Dvl disheveled protein
E-C excitation-contraction
ECM extracellular matrix
EGF epidermal growth factor
eNOS endothelial NO synthase (also NOS3)
EPO erythropoietin
ET-1 endothelin-1
ETA,B ET-1 receptor A and B
Fz Frizzled
GEF guanine nucleotide exchange factor
GH growth hormone
G protein guanine nucleotide binding protein
GPCR G protein coupled receptor
GSK-3 glycogen synthase kinase-3
HAT histone acetyltransferase
HDAC histone deacetyla s e
H I F - 1 h y p o x i a i n d u c i b l e f a c t o r 1
H O - 1 h e m e o x y g e n a s e 1
I G F - 1 i n s u l i n - l i k e g r o w t h h o r m o n e 1
I L i n t e r l e u k i n
I P 3 i n o s i t o l - 1 , 4 , 5 - t r i p h o s p h a t e
J A K J a n u s k i n a s e
J N K c - J u n - N - t e r m i n a l k i n a s e
L I F L e u k e m i a i n h i b i t o r y f a c t o r
L I M P - 2 l y s o s o m a l i n t e g r a l m e m b r ane protein 2
LRP LDL receptorrelated protein
LV left ventricle
LTCC L-type Ca2+ channel
MAPK mitogen activated protein kinase
MCIP myocyte-enriched calcineurin-interacting protein
MCP-1 monocyte chemoattractant protein-1
MCT monocrotaline
2-ME methoxyestradiol
MHC myosin heavy chain
miRNA microRNA
MKK MAPK kinase
MKKK MKK kinase
MMP matrix metalloproteinase
MOMP mitochondrial outer membrane permeabilization
MR mineralocorticoid receptor
mTOR mammalian target of rapamycin
NCX Na/Ca2+ exchanger
NEP neutral endopeptidase
NFAT nuclear factor of activated T cells
NGF neuronal growth factor
NO nitric oxide
NPR-A, B, C natriuretic peptide receptors A, B and C
PAB pulmonary artery banding
PAH pulmonary arterial hypertension
PDE-5 phosphodiesterase type 5
PDGF platelet-derived growth factor
PG prostaglandin
pGC particulate guanylate cyclase
PGI2 prostacyclin
PI3K phosphatidylinositol-3 kinase
PIP2 phosphatidylinositol-4,5-biphosphate
PIP3 phosphatylinositol-3,4,5-triphosphate
PKA protein kinase A
P K C p r o t e i n k i n a s e C
P K G p r o t e i n k i n a s e G
P L C p h o s p h o l i p a s e C
P P A R p e r o x i s o m e p r o l i f e r a t o r - a c t i v a t e d r e c e p t o r
P T E N p h o s p h a t a s e a n d t e n s i n h o m o l o g o n c h r o m o s o m e 1 0
R A S r e n i n - a n g i o t e n s i n s y s t e m
R N S r e a c t i v e n i t r o g e n s p e c i e s
R O C K R h o k i n a s e
R O S r e a c t i v e o x y g e n s p e c i e s
R T K r e c e p t o r t y r o s i n e k i n a s e
R V r i g h t v e n t r i c l e
R y R R y a n o d i n e r e c e p t o r
S E R C A s a r c o p l a s m i c C a 2 + A T P a s e
s G C s o l u b l e g u a n y l a t e c y c l a s e
S i r 2 s i l e n t i n f o r m a t i o n r e g u l a t o r 2
S N O N O - m o d i f i e d c y s t e i n e t h i o l s
S O D s u p e r o x i d e d i s m u t a s e
S R s a r c o p l a s m i c r e t i c u l u m
S R F s e r u m r e s p o n s e f a c t o r
S T A R S s t r i a t e d m u s c l e a c t i v a t o r o f r h o s i g n a l i n g
S T A T - 3 s i g n a l t r a n s d u c e r a n d a c t i v a t o r o f t r a n s c r i p t i o n 3
T A C t r a n s v e r s e a o r t i c c o n s t r i c t i o n
T A K 1 T G F - - a c t i v a t e d k i n a s e 1
T c f / L e f T - c e l l f a c t o r / L y m p h o c y t e e n h a n c e r f a c t o r
T G F - 1 t r a n s f o r m i n g g r o w t h f a c t o r 1
T N F t u m o r n e c r o s i s f a c t o r
T R F - 1 , 2 t e l o m e r i c b i n d i n g p r o t e i n s 1 a n d 2
T r x t h i o r e d o x i n
V E G F v a s c u l a r e n d o t h e l i a l g r o w t h f a c t o r
V H L v o n H i p p e l - L i n d a u p r o t e i n
X O x a n t h i n e o x i d a s e
1 . A n i m a l m o d e l s for the study of pulmonary hypertension and right heart failure
The degree of RV adaptation and failure varies substantially in current PAH animal models (see table e1). Presently used animal models to study the vascular changes in pulmonary hypertension all have their limitations in the study of PAH associated right heart failure. Chronic hypoxia is associated with increased RV afterload due to hypoxic pulmonary vasoconstriction and pulmonary vascular smooth muscle cell hyperplasia ADDIN REFMGR.CITE Rabinovitch1981544Age and sex influence on pulmonary hypertension of chronic hypoxia and on recoveryJournal544Age and sex influence on pulmonary hypertension of chronic hypoxia and on recoveryRabinovitch,M.Gamble,W.J.Miettinen,O.S.Reid,L.1981/1AdultAge FactorsAnimalsAnoxiabloodBlood PressureCardiomegalyChronic DiseaseFemaleHemodynamic ProcessesHypertensionHypertension,PulmonaryhypoxiaMalemuscleMuscle,Smooth,VascularOxygenphysiopathologyPulmonary ArteryPulmonary Circulationpulmonary hypertensionRatsSex FactorsNot in FileH62H72Am.J.Physiol.2401Am.J.Physiol.1Partovian1998526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionJournal526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionPartovian,C.Adnot,S.Eddahibi,S.Teiger,E.Levame,M.Dreyfus,P.Raffestin,B.Frelin,C.1998/12analysisAnimalsAnoxiaCapillarieschemically inducedChronic DiseasecomplicationsEndothelial Growth FactorsetiologygeneticsheartHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyhypoxiaLungLymphokinesMalemetabolismmodelmonocrotalineMyocardiumOrgan SizepathologyPerfusionphysiologyphysiopathologypulmonary hypertensionRatsRats,Wistarremodelingright ventricleRNA,MessengerVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVEGFNot in FileH1948H1956Am.J.Physiol.2756 Pt 2Am.J.Physiol.1Fagan2004251Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinaseJournal251Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinaseFagan,Karen A.Oka,MasahikoBauer,Natalie R.Gebb,Sarah A.Ivy,D.DunbarMorris,Kenneth G.McMurtry,Ivan F.2004/10/1hypoxiahypoxic pulmonary vasoconstrictionnitric oxidepulmonary hypertensionRhoNot in FileL656L664Am J Physiol Lung Cell Mol Physiol2874http://ajplung.physiology.org/cgi/content/abstract/287/4/L656AJP - Lung Cellular and Molecular PhysiologyAm J Physiol Lung Cell Mol Physiol1Abe2006730Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in miceJournal730Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in miceAbe,K.Tawara,S.Oi,K.Hizume,T.Uwatoku,T.Fukumoto,Y.Kaibuchi,K.Shimokawa,H.2006/12ArteriosclerosiseNOSetiologyfasudilHypertensionhypertrophyMicemodelmuscleMuscle Cellsnitric oxideNitric Oxide SynthaseNOPhosphorylationpulmonary hypertensionRatsResearchRhoNot in File280285J Cardiovasc Pharmacol486Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, JapanPM:17204906J Cardiovasc Pharmacol11-4. However, the impossibility to differentiate between the effects of pressure overload and the direct effects of hypoxia limits extrapolation from this model to right heart failure in PAH. The toxic effects of monocrotaline (MCT), a pyrrolizidine alkaloid that causes pulmonary vasculitis and subsequently vascular remodeling, are generally assumed to be pulmonary specific ADDIN REFMGR.CITE Partovian1998526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionJournal526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionPartovian,C.Adnot,S.Eddahibi,S.Teiger,E.Levame,M.Dreyfus,P.Raffestin,B.Frelin,C.1998/12analysisAnimalsAnoxiaCapillarieschemically inducedChronic DiseasecomplicationsEndothelial Growth FactorsetiologygeneticsheartHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyhypoxiaLungLymphokinesMalemetabolismmodelmonocrotalineMyocardiumOrgan SizepathologyPerfusionphysiologyphysiopathologypulmonary hypertensionRatsRats,Wistarremodelingright ventricleRNA,MessengerVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVEGFNot in FileH1948H1956Am.J.Physiol.2756 Pt 2Am.J.Physiol.1Werchan1989642Right ventricular performance after monocrotaline-induced pulmonary hypertensionJournal642Right ventricular performance after monocrotaline-induced pulmonary hypertensionWerchan,P.M.Summer,W.R.Gerdes,A.M.McDonough,K.H.1989/5AnimalsBlood Pressurecardiac outputCardiomegalychemically inducedetiologyheartHeart VentriclesHypertensionHypertension,PulmonaryhypertrophyMalemonocrotalineMyocardiumNOOrgan SizepathologyphysiologyphysiopathologyPressurepulmonary hypertensionPyrrolizidine AlkaloidsRatsRats,Inbred Strainsright ventricleVentricular FunctionNot in FileH1328H1336Am.J Physiol.2565 Pt 2Am.J Physiol.1Farhat1993543Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in ratsJournal543Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in ratsFarhat,M.Y.Chen,M.F.Bhatti,T.Iqbal,A.Cathapermal,S.Ramwell,P.W.1993/10AnimalsBehavior,AnimalBody Weightchemically induceddrug effectsDrug ImplantsEstradiolHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyHypertrophy,Right VentricularLungMacrophagesMalemonocrotalineMyocardiumNOOrgan SizepathologypharmacologyphysiologyphysiopathologyPulmonary ArteryPulmonary Circulationpulmonary edemapulmonary hypertensionRatsRats,Sprague-Dawleyright ventricleNot in File719723Br.J.Pharmacol.1102Br.J.Pharmacol.1Abe2004244Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in RatsJournal244Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in RatsAbe,KohtaroShimokawa,HiroakiMorikawa,KeikoUwatoku,ToyokazuOi,KeijiMatsumoto,YasuharuHattori,TsuyoshiNakashima,YutakaKaibuchi,KozoSueishi,KatsuoTakeshit,Akira2004/2/20apoptosispulmonary hypertensionRhomonocrotalineNot in File385393Circ Res943http://circres.ahajournals.org/cgi/content/abstract/94/3/385Circ Res1Monnet2005643Animal models of heart failure: what is new?Journal643Animal models of heart failure: what is new?Monnet,E.Chachques,J.C.2005/4AnimalsBlood PressureCardiac VolumeCardiomyopathy,DilatedclinicalcomplicationsDisease Models,AnimalDoxorubicinetiologyheartheart failureHeart Failure,CongestiveHeart TransplantationHumansImipramineLigationmodelmonocrotalinemortalityMyocardial IschemiapathologysurgerysurvivaltherapytoxicitytransplantationNot in File14451453Ann.Thorac.Surg.794Ann.Thorac.Surg.1Schermuly2005242Reversal of experimental pulmonary hypertension by PDGF inhibitionJournal242Reversal of experimental pulmonary hypertension by PDGF inhibitionSchermuly,Ralph TheoDony,EvaGhofrani,Hossein ArdeschirPullamsetti,SoniSavai,RajkumarRoth,MarkusSydykov,AkylbekLai,Ying JuWeissmann,NorbertSeeger,WernerGrimminger,Friedrich2005/10/1imatinibPDGFpulmonary hypertensionNot in File28112821J.Clin.Invest.11510http://www.jci.org/cgi/content/abstract/115/10/2811Journal of Clinical InvestigationJ.Clin.Invest.1Merklinger2005628Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertensionJournal628Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertensionMerklinger,S.L.Jones,P.L.Martinez,E.C.Rabinovitch,M.2005/7Animalsantagonists & inhibitorsapoptosisclinicalcytologydrug effectsdrug therapyEnzyme InhibitorsHypertensionHypertension,PulmonaryhypertrophyIntegrin alphaVbeta3MaleMetalloproteasesmethodsmonocrotalinemortalitymuscleMuscle,Smooth,VascularMyocytes,Smooth MuscleNOOrgan Culture TechniquesPAHpharmacologyphysiologyPressureProtease InhibitorsPulmonary Arterypulmonary hypertensionRatsRats,Sprague-DawleyReceptor,Epidermal Growth Factorsurvivaltherapeutic usetherapyTyrosineTyrphostinsNot in File423431Circulation.1123Circulation.1Kajiya2007580Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive ratsJournal580Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive ratsKajiya,M.Hirota,M.Inai,Y.Kiyooka,T.Morimoto,T.Iwasaki,T.Endo,K.Mohri,S.Shimizu,J.Yada,T.Ogasawara,Y.Naruse,K.Ohe,T.Kajiya,F.2007/1/12Cardiovascular Physiologyheartheart failureHomeostasisHypertensionhypertrophyMalemonocrotalinenitric oxideNOphysiologypulmonary hypertensionRatsStressVasodilationNot in File2737-2744Am.J.Physiol Heart Circ.Physiol.2926Am.J.Physiol Heart Circ.Physiol.1Kimura2007742Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac HypertrophyJournal742Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac HypertrophyKimura,KensukeIeda,MasakiKanazawa,HideakiYagi,TakashiTsunoda,MakotoNinomiya,Shin ichiKurosawa,HiroyukiYoshimi,KenjiMochizuki,HidekiYamazaki,KazutoOgawa,SatoshiFukuda,Keiichi2007/6/22Angiotensin IIendothelin-1hearthypertrophyinnervationmonocrotalineNorepinephrinepulmonary hypertensionRatsright ventricleNot in File17551764Circ Res10012http://circres.ahajournals.org/cgi/content/abstract/100/12/1755Circ Res12;5-12. However, MCT is also used to generate liver damage and hepatic veno-occlusive disease ADDIN REFMGR.CITE Shah2005723Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanismJournal723Monocrotaline pyrrole-induced endothelial cell megalocytosis involves a Golgi blockade mechanismShah,MehulPatel,KiritSehgal,Pravin B.2005/4/1AlkaloidsEndothelial CellsEpithelial CellsHypertensionKidneyLiverLungMitosismonocrotalinemuscleMuscle CellsPASMCPhenotypePhosphorylationpulmonary hypertensionPyrrolizidine AlkaloidsNot in FileC850C862Am J Physiol Cell Physiol2884http://ajpcell.physiology.org/cgi/content/abstract/288/4/C850AJP - Cell PhysiologyAm J Physiol Cell Physiol113. It is possible that the pro-inflammatory and pro-coagulant responses elicited by MCT-induced pulmonary vaculitis have systemic effects and contribute to heart failure. In fact, Akhavein et al recently demonstrated that shortly after MCT administration (even before pulmonary hypertension develops), extensive inflammatory changes can be seen in both ventricles and that these changes are associated with depressed contractile function, especially in the LV ADDIN REFMGR.CITE Akhavein2007748Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult ratsJournal748Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult ratsAkhavein,F.-Michel,E.JeanSeifert,E.Rohlicek,C.V.2007/7/1monocrotalineMyocarditispulmonary hypertensionRatsVentricular FunctionNot in File287295J Appl Physiol1031http://jap.physiology.org/cgi/content/abstract/103/1/287Journal of Applied PhysiologyJ Appl Physiol114. When MCT is combined with aortocaval shunting, the developing pulmonary vascular changes more closely resemble those of human severe PAH ADDIN REFMGR.CITE van Albada2006649Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertensionJournal649Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertensionvan Albada,M.E.Berger,R.M.Niggebrugge,M.van,Veghel R.Cromme-Dijkhuis,A.H.Schoemaker,R.G.2006/11/7AnimalsArachidonic AcidAspirinBlood Pressureblood supplyCapillariesCardiologycongenitalcontractilityDisease Models,Animaldrug effectsdrug therapyechocardiographyGene ExpressiongeneticsheartHeart VentriclesHypertensionHypertension,PulmonaryhypertrophyiloprostLungMalemetabolismmodelmonocrotalinemortalityMyocardiumOrgan SizepathologyphysiopathologyPlatelet Aggregation InhibitorsPressureprostacyclinPulmonary ArteryPulmonary Circulationpulmonary hypertensionRatsRats,WistarReceptors,Vascular Endothelial Growth FactorremodelingshuntSurvival Ratetherapeutic usetherapyVascular Endothelial Growth Factor AVentricular RemodelingNot in File107116Eur.J Pharmacol.5491-3Eur.J Pharmacol.115. Since right heart failure in this model of flow-associated PAH comes about by a combination of pressure and volume overload, this model may reflect failure in congenital heart disease, but not RV failure in most types of human PAH. More recently a model of severe angioproliferative pulmonary hypertension has been developed based on a single administration of the vascular endothelial growth factor (VEGF) receptor blocker SU5416 ADDIN REFMGR.CITE Taraseviciene-Stewart2001264Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertensionJournal264Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertensionTaraseviciene-Stewart,L.kasahara,YasunoriAlger,LoriHirth,PeterMcMahon,GeraldWaltenberger,JohannesVoelkel,Norbert F.Tuder,Rubin M.2001/2/1hypoxiapulmonary hypertensionVEGFapoptosisNot in File427438FASEB J.152http://www.fasebj.org/cgi/content/abstract/15/2/427The FASEB JournalFASEB J.1Taraseviciene-Stewart2006209Simvastatin Causes Endothelial Cell Apoptosis and Attenuates Severe Pulmonary HypertensionJournal209Simvastatin Causes Endothelial Cell Apoptosis and Attenuates Severe Pulmonary HypertensionTaraseviciene-Stewart,LaimuteScerbavicius,RobertasChoe,Kang HyeonCool,CarlyneWood,KathyTuder,Rubin M.Burns,NanaKasper,MichaelVoelkel,Norbert F.2006/5/12apoptosisendotheliumpulmonary hypertensionstatinNot in File00491Am J Physiol Lung Cell Mol Physiolhttp://ajplung.physiology.org/cgi/content/abstract/00491.2005v1AJP - Lung Cellular and Molecular PhysiologyAm J Physiol Lung Cell Mol Physiol1Oka2007735Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in ratsJournal735Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in ratsOka,M.Homma,N.Taraseviciene-Stewart,L.Morris,K.G.Kraskauskas,D.Burns,N.Voelkel,N.F.McMurtry,I.F.2007/3/301-(5-Isoquinolinesulfonyl)-2-MethylpiperazineAdultanalogs & derivativesAnimalsAnoxiaantagonists & inhibitorschemically inducedDisease Models,AnimalDisease Progressiondrug effectsenzymologyfasudilHypertensionHypertension,PulmonaryhypoxiailoprostIndolesIntracellular Signaling Peptides and ProteinsLungMalemetabolismmodelMyosin-Light-Chain PhosphataseNOOrgan Culture TechniquesPAHPeptides,CyclicpharmacologyPhosphorylationphysiopathologyPressureProtein-Serine-Threonine KinasesPulmonary Arterypulmonary hypertensionPyrrolesRatsRats,Sprague-DawleyReceptor,Endothelin AremodelingResearchRhoVascular Endothelial Growth Factor Receptor-2Vascular ResistanceVasoconstrictionVasodilator AgentsNot in File923929Circ.Res.1006Circ.Res.116-18. This drug induces pulmonary endothelial cell apoptosis and secondary vascular remodeling, but the specificity of SU5416 for the pulmonary endothelium has not been determined. Both SU5416 and MCT may affect the myocardial microcirculation directly.
Pulmonary artery banding (PAB) has no other direct effects than increasing afterload, but RV adaptation in this model is very dose and species dependent. Cat and dog PAB models have been used incidentally to study the RV response to acute and chronic increases in afterload ADDIN REFMGR.CITE Thompson1998639Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overloadJournal639Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overloadThompson,J.T.Rackley,M.S.O'Brien,T.X.1998/5AdultAnimalsAtrial Natriuretic FactorBlood PressureCatsDnageneticsheartHomeodomain ProteinshypertrophyHypertrophy,Right VentricularmodelpathologyphysiopathologyPressurePulmonary ArteryResearchRnaTranscription FactorsUp-RegulationVentricular PressureNot in FileH1569H1573Am.J Physiol.2745 Pt 2Am.J Physiol.1Orito2004640Time course sequences of angiotensin converting enzyme and chymase-like activities during development of right ventricular hypertrophy induced by pulmonary artery constriction in dogsJournal640Time course sequences of angiotensin converting enzyme and chymase-like activities during development of right ventricular hypertrophy induced by pulmonary artery constriction in dogsOrito,K.Yamane,T.Kanai,T.Fujii,Y.Wakao,Y.Matsuda,H.2004/7/16AnimalsbloodBlood Flow VelocityChymasesConstrictionConstriction,PathologicDisease Models,AnimalDogsechocardiographyenzymologyfibrosisheartHeart VentriclesHistological TechniqueshypertrophyHypertrophy,Right VentricularmetabolismpathologyPeptidyl-Dipeptidase ApharmacologyphysiologyphysiopathologyPressurePulmonary ArteryradiographyReninright ventricleSerine EndopeptidasesTime FactorsVentricular PressureNot in File11351145Life Sci.759Life Sci.1Kerbaul2007561How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertensionJournal561How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertensionKerbaul,F.Brimioulle,S.Rondelet,B.Dewachter,C.Hubloue,I.Naeije,R.2007/4/15cardiac outputcontractilityDogsepoprostenolheartheart failureHypertensionmethodsmodelphysiologyprostacyclinpulmonary hypertensionright ventricletherapyVascular ResistanceNot in File846850Am.J.Respir.Crit Care Med.1758Am.J.Respir.Crit Care Med.1Saito1991578Oxygen metabolism of the hypertrophic right ventricle in open chest dogsJournal578Oxygen metabolism of the hypertrophic right ventricle in open chest dogsSaito,D.Tani,H.Kusachi,S.Uchida,S.Ohbayashi,N.Marutani,M.Maekawa,K.Tsuji,T.Haraoka,S.1991/9AnimalsbloodCardiomegalyCoronary VesselsDisease Models,AnimalDogsdrug effectsFemalehypertrophyIsoproterenolMalemetabolismMyocardiumNOOxygenOxygen Consumptionoxygen extractionpharmacologyphysiologyPulmonary ArteryRegional Blood Flowright ventricleSodiumVentricular PressureNot in File731739Cardiovasc.Res.259Cardiovasc.Res.119-22. Although rabbit and rodent PAB models are useful to study acute increases in RV afterload, the high short-term mortality rates in some of these models (e.g. 50% after one week of PAB in rabbits) questions their suitability to study the development of right heart failure in PAH ADDIN REFMGR.CITE Adachi1995648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingJournal648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingAdachi,S.Ito,H.Ohta,Y.Tanaka,M.Ishiyama,S.Nagata,M.Toyozaki,T.Hirata,Y.Marumo,F.Hiroe,M.1995/1ActinsanalysisAnimalsAtrial Natriuretic Factorbiosynthesisbrain natriuretic peptideGene ExpressionHeart VentricleshypertrophyHypertrophy,Right VentricularIn Situ HybridizationMalemetabolismmodelMyocardiumNatriuretic Peptide,BrainNatriuretic PeptidesNerve Tissue ProteinsOrgan SpecificityPeptidesphysiologyphysiopathologyPressureProbabilityPulmonary ArteryRatsRats,Wistarright ventricleRNA,MessengerStressSystoleVentricular PressureNot in FileH162H169Am.J Physiol.2681 Pt 2Am.J Physiol.1Bishop1994645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadJournal645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadBishop,J.E.Rhodes,S.Laurent,G.J.Low,R.B.Stirewalt,W.S.1994/10analysisAnimalsbiosynthesisBlotting,NorthernCollagenGene ExpressiongeneticsheartHeart VentricleshypertrophyHypertrophy,Right VentricularLungMalemetabolismmethodsPressureProcollagenPulmonary ArteryRabbitsright ventricleRNA,MessengerNot in File15811585Cardiovasc.Res.2810Cardiovasc.Res.1Matsui1995637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitJournal637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitMatsui,H.MacLennan,D.H.Alpert,N.R.Periasamy,M.1995/1ActinsAnimalsCalcium ChannelsCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCardiomegalycomplicationsdiastolic functionetiologyGene ExpressiongeneticsheartHypertensionhypertrophyMalemetabolismmuscleMuscle ProteinsMyocardiumphysiologyPressureProteinsPulmonary ArteryRabbitsRNA,MessengerRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumNot in FileC252C258Am.J Physiol.2681 Pt 1Am.J Physiol.1LekanneDeprez1998641Changing patterns of gene expression in the pulmonary trunk-banded rat heartJournal641Changing patterns of gene expression in the pulmonary trunk-banded rat heartLekanneDeprez,R.H.van den Hoff,M.J.de Boer,P.A.Ruijter,P.M.Maas,A.A.Chamuleau,R.A.Lamers,W.H.Moorman,A.F.1998/9AmmoniaAnimalsAtrial Natriuretic FactorBiological MarkersbiosynthesisbloodBlotting,NortherncalciumCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCollagenConstrictionCoronary CirculationdiagnosisfibrosisGene Expressiongeneticsheartheart failureHeart Failure,CongestivehypertrophyIn Situ HybridizationLiverMalemetabolismmodelMyocardiumPulmonary ArteryPulmonary CirculationRatsRats,Wistarright ventricleRNA,MessengerStresssurgeryNot in File18771888J Mol.Cell Cardiol.309J Mol.Cell Cardiol.1Ikeda1999647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingJournal647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingIkeda,S.Hamada,M.Hiwada,K.1999analysisAnimalsapoptosisbcl-2-Associated X ProteinBody WeightConstrictioncytologyDNA FragmentationGenes,p53geneticsHeart VentriclesHypertrophy,Right VentricularImmunohistochemistryIn Situ Nick-End LabelingMalemetabolismMyocardiumphysiologyPressureProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRatsRats,Sprague-Dawleyright ventricleRNA,MessengersurgeryTime FactorsTumor Suppressor Protein p53Up-RegulationVentricular PressureNot in File925933Life Sci.659Life Sci.1Rouleau2001636Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathwayJournal636Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathwayRouleau,J.L.Kapuku,G.Pelletier,S.Gosselin,H.Adam,A.Gagnon,C.Lambert,C.Meloche,S.2001/8/21Angiotensin IIAngiotensin-Converting Enzyme InhibitorsAnimalsantagonists & inhibitorscontractilityDisease Models,AnimalDose-Response Relationship,Drugdrug effectsdrug therapyElectric StimulationGTP-Binding ProteinsheartHemodynamic ProcesseshypertrophyKininsLosartanMalemetabolismmethodsmodelmuscleMyocardial ContractionMyocardiumNOOrgan SizePapillary MusclespathologypharmacologyPhenylephrinephysiopathologyPressureProtein SubunitsPulmonary ArteryRabbitsRamiprilReceptor,Angiotensin,Type 1Receptor,Angiotensin,Type 2Receptors,BradykininReceptors,Angiotensinright ventricleSignal TransductionVentricular Dysfunction,RightVentricular PressureNot in File939944Circulation.1048Circulation.1Emani2001638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingJournal638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingEmani,S.M.Shah,A.S.White,D.C.Glower,D.D.Koch,W.J.2001/11Animalsbeta-Adrenergic Receptor Kinasebeta-GalactosidaseCarrier ProteinsclinicalGene Therapygene transferHeart VentricleshypertrophymethodsmortalitypathologyPeptidesPressurePulmonary ArteryRabbitsRecombinant ProteinssurgerysurvivalSurvival Ratetherapeutic usetherapyTransgenesVentricular Dysfunction,RightVentricular PressureNot in File16571661Ann.Thorac.Surg.725Ann.Thorac.Surg.1Bar2003644Upregulation of embryonic transcription factors in right ventricular hypertrophyJournal644Upregulation of embryonic transcription factors in right ventricular hypertrophyBar,H.Kreuzer,J.Cojoc,A.Jahn,L.2003/9AdultAnimalsAtrial Natriuretic FactorBasic Helix-Loop-Helix Transcription FactorsBinding SitesBiological MarkersBlotting,WesternCardiologyDisease Models,AnimalDNA-Binding ProteinsGATA4 Transcription FactorGene ExpressionheartHumanshypertrophyHypertrophy,Right VentricularImmunohistochemistryLigationMalemetabolismMicroscopy,FluorescencemodelMyocardiumMyogenic Regulatory FactorsPressureProteinsPulmonary ArteryRatsRats,Sprague-Dawleyright ventricleTranscription FactorsUp-RegulationZebrafish ProteinsNot in File285294Basic Res.Cardiol.985Basic Res.Cardiol.1Braun2003646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesJournal646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesBraun,M.U.Szalai,P.Strasser,R.H.Borst,M.M.2003/9/1analogs & derivativesanalysisAngiotensin-Converting Enzyme InhibitorsAnimalsapoptosisbcl-2-Associated X ProteinCalcineurinCardiologyCaspase 3chemistryConstriction,PathologicCytosoldrug therapyenzymologyhypertrophyHypertrophy,Right VentricularImmunoblottingIsoenzymesMalemetabolismmethodsMyocardiumNOpathologypharmacologyPressureProtein Kinase CProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRamiprilRatsRats,WistarremodelingRenin-Angiotensin SystemNot in File658667Cardiovasc.Res.593Cardiovasc.Res.123-31. The rodent RV subjected to PAB displays many changes that have been originally described in the pressure overloaded LV: fetal gene re-expressi o n , - a d r e n e r g i c r e c e p t o r ( - A R ) d y s r e g u l a t i o n , a l t e r e d e x p r e s s i o n o f s a r c o p l a s m i c r e t i c u l u m ( S R ) p r o t e i n s , m y o c a r d i a l f i b r o s i s a n d i n c r e a s e d a p o p t o s i s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > A d a c h i < / A u t h o r > < Y e a r > 1 9 9 5 < / Y e a r > < R e c N u m > 6 4 8 < / R e c N u m > < I D T e x t > D i stribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingJournal648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingAdachi,S.Ito,H.Ohta,Y.Tanaka,M.Ishiyama,S.Nagata,M.Toyozaki,T.Hirata,Y.Marumo,F.Hiroe,M.1995/1ActinsanalysisAnimalsAtrial Natriuretic Factorbiosynthesisbrain natriuretic peptideGene ExpressionHeart VentricleshypertrophyHypertrophy,Right VentricularIn Situ HybridizationMalemetabolismmodelMyocardiumNatriuretic Peptide,BrainNatriuretic PeptidesNerve Tissue ProteinsOrgan SpecificityPeptidesphysiologyphysiopathologyPressureProbabilityPulmonary ArteryRatsRats,Wistarright ventricleRNA,MessengerStressSystoleVentricular PressureNot in FileH162H169Am.J Physiol.2681 Pt 2Am.J Physiol.1Matsui1995637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitJournal637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitMatsui,H.MacLennan,D.H.Alpert,N.R.Periasamy,M.1995/1ActinsAnimalsCalcium ChannelsCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCardiomegalycomplicationsdiastolic functionetiologyGene ExpressiongeneticsheartHypertensionhypertrophyMalemetabolismmuscleMuscle ProteinsMyocardiumphysiologyPressureProteinsPulmonary ArteryRabbitsRNA,MessengerRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumNot in FileC252C258Am.J Physiol.2681 Pt 1Am.J Physiol.1Bishop1994645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadJournal645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadBishop,J.E.Rhodes,S.Laurent,G.J.Low,R.B.Stirewalt,W.S.1994/10analysisAnimalsbiosynthesisBlotting,NorthernCollagenGene ExpressiongeneticsheartHeart VentricleshypertrophyHypertrophy,Right VentricularLungMalemetabolismmethodsPressureProcollagenPulmonary ArteryRabbitsright ventricleRNA,MessengerNot in File15811585Cardiovasc.Res.2810Cardiovasc.Res.1Bar2003644Upregulation of embryonic transcription factors in right ventricular hypertrophyJournal644Upregulation of embryonic transcription factors in right ventricular hypertrophyBar,H.Kreuzer,J.Cojoc,A.Jahn,L.2003/9AdultAnimalsAtrial Natriuretic FactorBasic Helix-Loop-Helix Transcription FactorsBinding SitesBiological MarkersBlotting,WesternCardiologyDisease Models,AnimalDNA-Binding ProteinsGATA4 Transcription FactorGene ExpressionheartHumanshypertrophyHypertrophy,Right VentricularImmunohistochemistryLigationMalemetabolismMicroscopy,FluorescencemodelMyocardiumMyogenic Regulatory FactorsPressureProteinsPulmonary ArteryRatsRats,Sprague-Dawleyright ventricleTranscription FactorsUp-RegulationZebrafish ProteinsNot in File285294Basic Res.Cardiol.985Basic Res.Cardiol.1Braun2003646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesJournal646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesBraun,M.U.Szalai,P.Strasser,R.H.Borst,M.M.2003/9/1analogs & derivativesanalysisAngiotensin-Converting Enzyme InhibitorsAnimalsapoptosisbcl-2-Associated X ProteinCalcineurinCardiologyCaspase 3chemistryConstriction,PathologicCytosoldrug therapyenzymologyhypertrophyHypertrophy,Right VentricularImmunoblottingIsoenzymesMalemetabolismmethodsMyocardiumNOpathologypharmacologyPressureProtein Kinase CProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRamiprilRatsRats,WistarremodelingRenin-Angiotensin SystemNot in File658667Cardiovasc.Res.593Cardiovasc.Res.1Ikeda1999647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingJournal647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingIkeda,S.Hamada,M.Hiwada,K.1999analysisAnimalsapoptosisbcl-2-Associated X ProteinBody WeightConstrictioncytologyDNA FragmentationGenes,p53geneticsHeart VentriclesHypertrophy,Right VentricularImmunohistochemistryIn Situ Nick-End LabelingMalemetabolismMyocardiumphysiologyPressureProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRatsRats,Sprague-Dawleyright ventricleRNA,MessengersurgeryTime FactorsTumor Suppressor Protein p53Up-RegulationVentricular PressureNot in File925933Life Sci.659Life Sci.1Emani2001638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingJournal638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingEmani,S.M.Shah,A.S.White,D.C.Glower,D.D.Koch,W.J.2001/11Animalsbeta-Adrenergic Receptor Kinasebeta-GalactosidaseCarrier ProteinsclinicalGene Therapygene transferHeart VentricleshypertrophymethodsmortalitypathologyPeptidesPressurePulmonary ArteryRabbitsRecombinant ProteinssurgerysurvivalSurvival Ratetherapeutic usetherapyTransgenesVentricular Dysfunction,RightVentricular PressureNot in File16571661Ann.Thorac.Surg.725Ann.Thorac.Surg.1LekanneDeprez1998641Changing patterns of gene expression in the pulmonary trunk-banded rat heartJournal641Changing patterns of gene expression in the pulmonary trunk-banded rat heartLekanneDeprez,R.H.van den Hoff,M.J.de Boer,P.A.Ruijter,P.M.Maas,A.A.Chamuleau,R.A.Lamers,W.H.Moorman,A.F.1998/9AmmoniaAnimalsAtrial Natriuretic FactorBiological MarkersbiosynthesisbloodBlotting,NortherncalciumCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCollagenConstrictionCoronary CirculationdiagnosisfibrosisGene Expressiongeneticsheartheart failureHeart Failure,CongestivehypertrophyIn Situ HybridizationLiverMalemetabolismmodelMyocardiumPulmonary ArteryPulmonary CirculationRatsRats,Wistarright ventricleRNA,MessengerStresssurgeryNot in File18771888J Mol.Cell Cardiol.309J Mol.Cell Cardiol.123-27;29-31. State-of-the-art research on LV pressure overload has moved forward to address the relative importance of these changes in the transition from compensated hypertrophy to heart failure, making use of transgenic knock-outs and constitutive activation of signaling pathways, with or without additional stressors like transverse aortic constriction (TAC) ADDIN REFMGR.CITE Hirota1999415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressJournal415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressHirota,H.Chen,J.Betz,U.A.Rajewsky,K.Gu,Y.Ross,J.,Jr.Muller,W.Chien,K.R.1999/4/16AnimalsAntigens,CDapoptosisBiomechanicsCardiomegalyCardiomyopathiesCell SurvivalCytokine Receptor gp130CytokinesembryologyetiologyFetal HeartGene Expression Regulation,Developmentalgeneticsgp130heartheart failureHeart Failure,CongestivehypertrophyMembrane GlycoproteinsMiceMice,KnockoutmuscleMyocardiumpathologyphysiologyphysiopathologyReceptors,CytokinesurvivalNot in File189198Cell.972Cell.1Tamura2000474Cardiac fibrosis in mice lacking brain natriuretic peptideJournal474Cardiac fibrosis in mice lacking brain natriuretic peptideTamura,N.Ogawa,Y.Chusho,H.Nakamura,K.Nakao,K.Suda,M.Kasahara,M.Hashimoto,R.Katsuura,G.Mukoyama,M.Itoh,H.Saito,Y.Tanaka,I.Otani,H.Katsuki,M.2000/4/11AnimalsBase SequencebiosynthesisBlood Pressurebrain natriuretic peptideclinicalExtracellular MatrixfibroblastFibroblastsfibrosisgeneticsheartheart failureHypertensionhypertrophyMiceMice,KnockoutMicroscopy,ElectronMyocardial InfarctionMyocardiumNatriuretic Peptide,BrainNOOligonucleotides,AntisensepathologyPhenotypephysiologyremodelingRNA,MessengerultrastructureVentricular PressureVentricular RemodelingWater-Electrolyte BalanceNot in File42394244Proc.Natl.Acad.Sci.U.S.A.978Proc.Natl.Acad.Sci.U.S.A.1Bueno2001597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoJournal597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoBueno,O.F.De Windt,L.J.Lim,H.W.Tymitz,K.M.Witt,S.A.Kimball,T.R.Molkentin,J.D.2001/1AdenoviridaeAnimalsAnimals,NewbornAtrial Natriuretic FactorBlotting,WesternCa(2+)-Calmodulin Dependent Protein KinaseCardiomegalyCatecholaminesCells,Culturedchemically inducedcytologyDNA,Recombinantdrug effectsendothelin-1enzymologyFemaleGene Expressiongene transferGene Transfer TechniquesGenetic VectorsgeneticshearthypertrophymetabolismMiceMice,TransgenicMyocardiumNOpharmacologyPhenylephrinePhosphorylationProtein-Tyrosine-PhosphataseRatsRNA,MessengerStressNot in File8896Circ.Res.881Circ.Res.1Takemoto2001430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyJournal430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyTakemoto,M.Node,K.Nakagami,H.Liao,Y.Grimm,M.Takemoto,Y.Kitakaze,M.Liao,J.K.2001/11Angiotensin IIAnimalsAntioxidantsAtrial Natriuretic FactorCardiomegalyCells,Cultureddrug effectsgeneticshearthypertrophyLeucinemetabolismMicemortalityMyocardiumNOOxidation-Reductionpharmacologyphysiologyprevention & controlPromoter Regions (Genetics)rac1 GTP-Binding ProteinRatsRats,Sprague-DawleyRhosimvastatinstatinSuperoxidestherapyNot in File14291437J.Clin.Invest.10810Journal of Clinical InvestigationJ.Clin.Invest.1Asakura2002667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyJournal667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyAsakura,M.Kitakaze,M.Takashima,S.Liao,Y.Ishikura,F.Yoshinaka,T.Ohmoto,H.Node,K.Yoshino,K.Ishiguro,H.Asanuma,H.Sanada,S.Matsumura,Y.Takeda,H.Beppu,S.Tada,M.Hori,M.Higashiyama,S.2002/1ADAM Proteinsanalogs & derivativesAngiotensin IIAnimalsantagonists & inhibitorsAorta,ThoracicCardiomegalyDisease Models,AnimalDisintegrinsdrug effectsdrug therapyEpidermal Growth FactorgeneticsGlycineGPCRGTP-Binding ProteinsheartHeart VentriclesHydroxamic AcidsHypertensionhypertrophyMaleMembrane ProteinsmetabolismMetalloendopeptidasesMicepharmacologyPhenylephrineProtease InhibitorsProtein Processing,Post-TranslationalRatsReceptor,Epidermal Growth FactorSignal TransductionsurgerySystoletherapeutic usetherapyTrans-Activation (Genetics)Not in File3540Nat.Med.81Nat.Med.1Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.1Hill2002596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionJournal596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionHill,J.A.Rothermel,B.Yoo,K.D.Cabuay,B.Demetroulis,E.Weiss,R.M.Kutschke,W.Bassel-Duby,R.Williams,R.S.2002/3/22Animalsantagonists & inhibitorsAortaBlood PressureBlotting,NorthernCalcineurinDNA,ComplementaryDose-Response Relationship,DrugechocardiographyElectroencephalographyheartHeart DiseasesHumanshypertrophyMalemetabolismMiceMice,TransgenicMyocardiumpathologyPressureProtein BindingProtein IsoformsRnaRNA,MessengerStressTime FactorsUp-RegulationNot in File1025110255J.Biol.Chem.27712Journal of Biological ChemistryJ.Biol.Chem.1Zahabi2003675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsJournal675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsZahabi,A.Picard,S.Fortin,N.Reudelhuber,T.L.Deschepper,C.F.2003/11/28Adenylate CyclaseAnimalsAortabiosynthesisBlood PressureBlotting,NorthernchemistryConstrictionCos CellsCyclic GMPDNA,Complementarydrug effectsechocardiographyenzymologyGene ExpressiongeneticsGuanylate CyclaseheartHypertensionhypertrophyIsoproterenolMalemetabolismMiceMice,Inbred C3HMice,Inbred C57BLMice,KnockoutMice,TransgenicmodelMyocardiumNOpathologyPeptidespharmacologyProtein Structure,TertiaryRatsReceptors,Atrial Natriuretic FactorremodelingResearchRNA,MessengerTissue DistributionTransfectionTransgenesNot in File4769447699J Biol.Chem.27848J Biol.Chem.1Hara2005563Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptorJournal563Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptorHara,A.Yuhki,K.Fujino,T.Yamada,T.Takayama,K.Kuriyama,S.Takahata,O.Karibe,H.Okada,Y.Xiao,C.Y.Ma,H.Narumiya,S.Ushikubi,F.2005/7/5analogs & derivativesanalysisAnimalsAortaBiological MarkersbloodCardiomegalyCell EnlargementcomplicationsCyclic AMPdeficiencyDisease Models,AnimalepoprostenoletiologyFemalefibrosisgeneticsheartHypertensionhypertrophymethodsMiceMice,KnockoutmodelMyocytes,CardiacNOpathologypharmacologyphysiologyReceptors,EpoprostenolRNA,MessengerNot in File8492Circulation.1121Circulation.1Takimoto2005528Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure loadJournal528Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure loadTakimoto,E.Champion,H.C.Li,M.Ren,S.Rodriguez,E.R.Tavazzi,B.Lazzarino,G.Paolocci,N.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/5analogs & derivativesAnimalsBiopterinCardiologyCardiomegalyenzymologyfibrosishearthypertrophyImmunoblottingmetabolismMicenitric oxideNitric Oxide SynthaseNitric Oxide Synthase Type IINitric Oxide Synthase Type IIINOOxidative Stressphysiologyreactive oxygen speciesremodelingStressVentricular Dysfunction,LeftNot in File12211231J.Clin.Invest.1155Journal of Clinical InvestigationJ.Clin.Invest.1Takimoto2005677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyJournal677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyTakimoto,E.Champion,H.C.Li,M.Belardi,D.Ren,S.Rodriguez,E.R.Bedja,D.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/21-Phosphatidylinositol 3-Kinase3',5'-Cyclic-GMP PhosphodiesteraseAnimalsAnimals,Newbornantagonists & inhibitorsBlood PressureCalcineurinCardiologyCardiomegalyConstrictionCyclic GMPCyclic GMP-Dependent Protein KinasesDNA-Binding Proteinsdrug effectsdrug therapyEnzyme ActivationenzymologyExtracellular Signal-Regulated MAP Kinasesgeneticsheartheart failureHemodynamic ProcesseshypertrophyMalemetabolismMiceMice,Inbred C57BLMice,TransgenicMyocardiumNFATC Transcription FactorsNuclear ProteinspathologypharmacologyPhosphodiesterase InhibitorsphysiologyPiperazinesPressureProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRatsRats,Sprague-Dawleyremodelingsildenafiltherapeutic useTranscription FactorsNot in File214222Nat.Med.112Nat.Med.1Perrino2006470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionJournal470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionPerrino,C.Naga Prasad,S.V.Mao,L.Noma,T.Yan,Z.Kim,H.S.Smithies,O.Rockman,H.A.2006/61-Phosphatidylinositol 3-KinaseAdrenergic beta-AntagonistsAnimalsantagonists & inhibitorsbeta-Adrenergic Receptor KinaseBlood PressureBlood VesselsCardiac Output,LowCardiomegalyCells,CulturedcytologyechocardiographyexerciseFemaleGene ExpressionGene Expression RegulationgeneticsheartHemodynamic ProcessesHumansHypertensionhypertrophyHypertrophy,Left VentricularmetabolismMetoprololMiceMice,Inbred C57BLMice,TransgenicMyocardiumpathologyPhenotypephysiologyphysiopathologyReceptors,Adrenergic,betaSignal TransductionStressNot in File15471560J.Clin.Invest.1166Journal of Clinical InvestigationJ.Clin.Invest.1Zhang2006287Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosisJournal287Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosisZhang,Ying MinBo,JacquelineTaffet,George E.Chang,JiangShi,JianjianReddy,Anilkumar K.Michael,Lloyd H.Schneider,Michael D.Entman,Mark L.Schwartz,Robert J.Wei,Lei2006/5/1myocardial fibrosisheartremodelingRhoNot in File916925FASEB J.207http://www.fasebj.org/cgi/content/abstract/20/7/916The FASEB JournalFASEB J.1Izumiya2006566Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overloadJournal566Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overloadIzumiya,Y.Shiojima,I.Sato,K.Sawyer,D.B.Colucci,W.S.Walsh,K.2006/5Adaptation,PhysiologicalAnimalsantagonists & inhibitorsAortaCapillariesCardiac Output,LowCardiomegalyCollagencomplicationsConstrictionCoronary CirculationechocardiographyetiologyfibrosisGene Transfer Techniquesgeneticsheartheart failureHypertensionhypertrophyImmunoglobulin Fc FragmentsMalemetabolismMiceMice,Inbred C57BLmodelMyocardial Contractionmyocardial fibrosisMyocardiumNOpathologyphysiopathologyUp-RegulationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2VEGFVentricular RemodelingNot in File887893Hypertension.475Hypertension.1Chang2006355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisJournal355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisChang,JiangXie,MinShah,Viraj R.Schneider,Michael D.Entman,Mark L.Wei,LeiSchwartz,Robert J.2006/9/26apoptosisheartheart failuremodelNot in File1449514500Proc.Natl.Acad.Sci.U.S.A.10339http://www.pnas.org/cgi/content/abstract/103/39/14495Proc.Natl.Acad.Sci.U.S.A.1Chen2006689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyJournal689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyChen,X.Shevtsov,S.P.Hsich,E.Cui,L.Haq,S.Aronovitz,M.Kerkela,R.Molkentin,J.D.Liao,R.Salomon,R.N.Patten,R.Force,T.2006/6Animalsbeta CateninCardiologyCardiomegalyCell CycleCell EnlargementCell ProliferationcytologydeficiencyetiologyGene DeletionGene Expressiongeneticsgrowth & developmentheartheart failurehypertrophyLymphoid Enhancer-Binding Factor 1metabolismMiceMice,Inbred C57BLMice,KnockoutMice,Mutant StrainsMice,TransgenicmodelMutationMyocytes,CardiacpathologyPhenotypeResearchSignal TransductionTCF Transcription FactorsTranscription FactorsNot in File44624473Mol.Cell Biol.2612Mol.Cell Biol.1Kuwahara2007618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityJournal618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityKuwahara,K.Pipes,G.C.McAnally,J.Richardson,J.A.Hill,J.A.Bassel-Duby,R.Olson,E.N.2007/5CalcineurinCardiomyopathiesCytoskeletal ProteinsCytoskeletonhearthypertrophymodelmusclepathologyPressureProteinsremodelingRhoStressNot in File13241334J.Clin.Invest.1175Journal of Clinical InvestigationJ.Clin.Invest.1Ohba2007508Upregulation of TRPC1 in the development of cardiac hypertrophyJournal508Upregulation of TRPC1 in the development of cardiac hypertrophyOhba,T.Watanabe,H.Murakami,M.Takahashi,Y.Iino,K.Kuromitsu,S.Mori,Y.Ono,K.Iijima,T.Ito,H.2007/3Angiotensin IIAtrial Natriuretic Factorbrain natriuretic peptideendothelin-1hearthypertrophyPhenylephrineRatsRnaNot in File498507J.Mol.Cell Cardiol.423J.Mol.Cell Cardiol.1Sano2007523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadJournal523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadSano,M.Minamino,T.Toko,H.Miyauchi,H.Orimo,M.Qin,Y.Akazawa,H.Tateno,K.Kayama,Y.Harada,M.Shimizu,I.Asahara,T.Hamada,H.Tomita,S.Molkentin,J.D.Zou,Y.Komuro,I.2007/3/22Animalsantagonists & inhibitorsAortaBlood PressureCardiac Output,LowCardiomegalyCoronary CirculationDisease Progressiongeneticsheartheart failurehypertrophyHypoxia-Inducible Factor 1,alpha SubunitmetabolismMiceNeovascularization,PathologicpathologyphysiopathologyTumor Suppressor Protein p53Not in File444448Nature.4467134Nature.1Trivedi2007606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityJournal606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityTrivedi,C.M.Luo,Y.Yin,Z.Zhang,M.Zhu,W.Wang,T.Floss,T.Goettlicher,M.Noppinger,P.R.Wurst,W.Ferrari,V.A.Abrams,C.S.Gruber,P.J.Epstein,J.A.2007/3AdultAnimalsbiosynthesisCardiomegalydeficiencyembryologyEnzyme ActivationenzymologyFetusgeneticsGlycogen Synthase Kinase 3heartheart failureHistone DeacetylaseshypertrophyIsoenzymesmetabolismMiceMice,KnockoutMice,TransgenicMolecular Sequence DataphysiologyRepressor ProteinsResearchSignal TransductionStressNot in File324331Nat.Med.133Nat.Med.1Care2007634MicroRNA-133 controls cardiac hypertrophyJournal634MicroRNA-133 controls cardiac hypertrophyCare,A.Catalucci,D.Felicetti,F.Bonci,D.Addario,A.Gallo,P.Bang,M.L.Segnalini,P.Gu,Y.Dalton,N.D.Elia,L.Latronico,M.V.Hoydal,M.Autore,C.Russo,M.A.Dorn,G.W.Ellingsen,O.Ruiz-Lozano,P.Peterson,K.L.Croce,C.M.Peschle,C.Condorelli,G.2007/5hearthypertrophyMicroRNAsmodeloncologySignal TransductionNot in File613618Nat.Med.135Nat.Med.1Van Rooij E.2007635Control of stress-dependent cardiac growth and gene expression by a microRNAJournal635Control of stress-dependent cardiac growth and gene expression by a microRNAVan Rooij E.Sutherland,L.B.Qi,X.Richardson,J.A.Hill,J.Olson,E.N.2007/4/27AnimalsCardiac MyosinsCardiomegalycontractilityDown-RegulationfibrosisGene DeletionGene ExpressionGene Expression RegulationgeneticsheartHeart DiseaseshypertrophyHypothyroidismIntronsmetabolismMiceMice,TransgenicMicroRNAsMyocardial ContractionMyocardiumMyocytes,CardiacMyosin Heavy ChainsOligonucleotide Array Sequence AnalysispathologyphysiologyphysiopathologyProteinsRatsSignal TransductionStressTranscription FactorsTriiodothyronineUp-RegulationVentricular MyosinsNot in File575579Science.3165824Science.1Jiang2007525Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in miceJournal525Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in miceJiang,Y.Reynolds,C.Xiao,C.Feng,W.Zhou,Z.Rodriguez,W.Tyagi,S.C.Eaton,J.W.Saari,J.T.Kang,Y.J.2007/3AnimalsantibodiesCardiomyopathiesCardiomyopathy,HypertrophicCells,CulturedChronic DiseasecomplicationsCopperdiet therapyDietary SupplementsDisease Models,Animaletiologyheartheart failureHIF-1alphaHumansHypertensionhypertrophyMaleMiceMice,Inbred C57BLmodelphysiopathologytherapeutic useVEGFNot in File657666J.Exp.Med.2043The Journal of Experimental MedicineJ.Exp.Med.1Dickey2007609Differential Regulation of Membrane Guanylyl Cyclases in Congestive Heart Failure: NPR-B, Not NPR-A, Is the Predominant Natriuretic Peptide Receptor in the Failing HeartJournal609Differential Regulation of Membrane Guanylyl Cyclases in Congestive Heart Failure: NPR-B, Not NPR-A, Is the Predominant Natriuretic Peptide Receptor in the Failing HeartDickey,D.M.Flora,D.R.Bryan,P.M.Xu,X.Chen,Y.Potter,L.R.2007/4/5bloodBlood PressureCardiologyheartheart failurehypertrophyMicepharmacologyPressureNot in File35183522Endocrinology.1487Endocrinology.1van de Schans2007686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyJournal686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyvan de Schans,V.van den Borne,S.W.Strzelecka,A.E.Janssen,B.J.van,der,VLangen,R.C.Wynshaw-Boris,A.Smits,J.F.Blankesteijn,W.M.2007/3Adaptor Proteins,Signal TransducinganalysisAnimalsAortic CoarctationAtrial Natriuretic Factorbeta CateninbiosynthesisCardiomegalycomplicationsConstrictionDisease Models,AnimaletiologyFemaleFrizzled ReceptorsGenesgeneticsGlycogen Synthase Kinase 3heartHypertensionhypertrophyMaleMiceMice,KnockoutNatriuretic PeptidespharmacologyPhosphoproteinsphysiologyphysiopathologyPressureProto-Oncogene Proteins c-aktResearchSignal TransductiontherapyultrasonographyWnt ProteinsNot in File473480Hypertension.493Hypertension.1Schroen2007690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophyJournal690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophySchroen,B.Leenders,J.J.van,Erk A.Bertrand,A.T.van,Loon M.van Leeuwen,R.E.Kubben,N.Duisters,R.F.Schellings,M.W.Janssen,B.J.Debets,J.J.Schwake,M.Hoydal,M.A.Heymans,S.Saftig,P.Pinto,Y.M.2007/5/21hypertrophyNot in Filei5J Cell Biol.1774J Cell Biol.1Sanada2007706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemJournal706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemSanada,S.Hakuno,D.Higgins,L.J.Schreiter,E.R.McKenzie,A.N.Lee,R.T.2007/6/1Angiotensin IIConstrictionfibroblastFibroblastsfibrosisheartheart failurehypertrophyMiceMyocardial InfarctionMyocardiumPhosphorylationPressureResearchsurvivalNot in File15381549J Clin.Invest.1176J Clin.Invest.1Sun2007739Tumor Necrosis Factor-{alpha} Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload StateJournal739Tumor Necrosis Factor-{alpha} Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload StateSun,MeiChen,ManyinDawood,FayezZurawska,UrszulaLi,Jeff Y.Parker,ThomasKassiri,ZamanehKirshenbaum,Lorrie A.Arnold,MalcolmKhokha,RamaLiu,Peter P.2007/3/20apoptosisExtracellular Matrixfibrosisheart failureTAChypertrophyMiceVentricular RemodelingTNFNot in File13981407Circulation11511http://circ.ahajournals.org/cgi/content/abstract/115/11/1398Circulation1Asaumi2007740Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in MiceJournal740Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in MiceAsaumi,YasuhideKagaya,YutakaTakeda,MorihikoYamaguchi,NobuhiroTada,HirokoIto,KentaOhta,JunShiroto,TakashiShirato,KunioMinegishi,NaokoShimokawa,Hiroaki2007/4/17CapillarieserythropoetinMiceMyocardiumTACVEGFNot in File20222032Circulation11515http://circ.ahajournals.org/cgi/content/abstract/115/15/2022Circulation132-60 and agonist infusion (e.g. catecholamines and angiotensin II (ATII), see table e2) ADDIN REFMGR.CITE Takemoto2001430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyJournal430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyTakemoto,M.Node,K.Nakagami,H.Liao,Y.Grimm,M.Takemoto,Y.Kitakaze,M.Liao,J.K.2001/11Angiotensin IIAnimalsAntioxidantsAtrial Natriuretic FactorCardiomegalyCells,Cultureddrug effectsgeneticshearthypertrophyLeucinemetabolismMicemortalityMyocardiumNOOxidation-Reductionpharmacologyphysiologyprevention & controlPromoter Regions (Genetics)rac1 GTP-Binding ProteinRatsRats,Sprague-DawleyRhosimvastatinstatinSuperoxidestherapyNot in File14291437J.Clin.Invest.10810Journal of Clinical InvestigationJ.Clin.Invest.1Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.1Koch1995422Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitorJournal422Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitorKoch,W.J.Rockman,H.A.Samama,P.Hamilton,R.A.Bond,R.A.Milano,C.A.Lefkowitz,R.J.1995/6/2Adenylate CyclaseAnimalsantagonists & inhibitorsbeta-Adrenergic Receptor KinaseBlood PressurecontractilityCyclic AMP-Dependent Protein Kinasesdrug effectsenzymologygeneticsGTP-Binding Proteinsheartheart failureIsoproterenolmetabolismMiceMice,TransgenicmodelMyocardial ContractionMyocardiumpharmacologyPhenotypephysiologyReceptors,Adrenergic,betaSarcolemmaVentricular PressureNot in File13501353Science.2685215Science.1Ohba2007508Upregulation of TRPC1 in the development of cardiac hypertrophyJournal508Upregulation of TRPC1 in the development of cardiac hypertrophyOhba,T.Watanabe,H.Murakami,M.Takahashi,Y.Iino,K.Kuromitsu,S.Mori,Y.Ono,K.Iijima,T.Ito,H.2007/3Angiotensin IIAtrial Natriuretic Factorbrain natriuretic peptideendothelin-1hearthypertrophyPhenylephrineRatsRnaNot in File498507J.Mol.Cell Cardiol.423J.Mol.Cell Cardiol.1Bueno2001597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoJournal597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoBueno,O.F.De Windt,L.J.Lim,H.W.Tymitz,K.M.Witt,S.A.Kimball,T.R.Molkentin,J.D.2001/1AdenoviridaeAnimalsAnimals,NewbornAtrial Natriuretic FactorBlotting,WesternCa(2+)-Calmodulin Dependent Protein KinaseCardiomegalyCatecholaminesCells,Culturedchemically inducedcytologyDNA,Recombinantdrug effectsendothelin-1enzymologyFemaleGene Expressiongene transferGene Transfer TechniquesGenetic VectorsgeneticshearthypertrophymetabolismMiceMice,TransgenicMyocardiumNOpharmacologyPhenylephrinePhosphorylationProtein-Tyrosine-PhosphataseRatsRNA,MessengerStressNot in File8896Circ.Res.881Circ.Res.1Trivedi2007606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityJournal606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityTrivedi,C.M.Luo,Y.Yin,Z.Zhang,M.Zhu,W.Wang,T.Floss,T.Goettlicher,M.Noppinger,P.R.Wurst,W.Ferrari,V.A.Abrams,C.S.Gruber,P.J.Epstein,J.A.2007/3AdultAnimalsbiosynthesisCardiomegalydeficiencyembryologyEnzyme ActivationenzymologyFetusgeneticsGlycogen Synthase Kinase 3heartheart failureHistone DeacetylaseshypertrophyIsoenzymesmetabolismMiceMice,KnockoutMice,TransgenicMolecular Sequence DataphysiologyRepressor ProteinsResearchSignal TransductionStressNot in File324331Nat.Med.133Nat.Med.1Asakura2002667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyJournal667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyAsakura,M.Kitakaze,M.Takashima,S.Liao,Y.Ishikura,F.Yoshinaka,T.Ohmoto,H.Node,K.Yoshino,K.Ishiguro,H.Asanuma,H.Sanada,S.Matsumura,Y.Takeda,H.Beppu,S.Tada,M.Hori,M.Higashiyama,S.2002/1ADAM Proteinsanalogs & derivativesAngiotensin IIAnimalsantagonists & inhibitorsAorta,ThoracicCardiomegalyDisease Models,AnimalDisintegrinsdrug effectsdrug therapyEpidermal Growth FactorgeneticsGlycineGPCRGTP-Binding ProteinsheartHeart VentriclesHydroxamic AcidsHypertensionhypertrophyMaleMembrane ProteinsmetabolismMetalloendopeptidasesMicepharmacologyPhenylephrineProtease InhibitorsProtein Processing,Post-TranslationalRatsReceptor,Epidermal Growth FactorSignal TransductionsurgerySystoletherapeutic usetherapyTrans-Activation (Genetics)Not in File3540Nat.Med.81Nat.Med.1Zahabi2003675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsJournal675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsZahabi,A.Picard,S.Fortin,N.Reudelhuber,T.L.Deschepper,C.F.2003/11/28Adenylate CyclaseAnimalsAortabiosynthesisBlood PressureBlotting,NorthernchemistryConstrictionCos CellsCyclic GMPDNA,Complementarydrug effectsechocardiographyenzymologyGene ExpressiongeneticsGuanylate CyclaseheartHypertensionhypertrophyIsoproterenolMalemetabolismMiceMice,Inbred C3HMice,Inbred C57BLMice,KnockoutMice,TransgenicmodelMyocardiumNOpathologyPeptidespharmacologyProtein Structure,TertiaryRatsReceptors,Atrial Natriuretic FactorremodelingResearchRNA,MessengerTissue DistributionTransfectionTransgenesNot in File4769447699J Biol.Chem.27848J Biol.Chem.1Baurand2007691Beta-catenin downregulation is required for adaptive cardiac remodelingJournal691Beta-catenin downregulation is required for adaptive cardiac remodelingBaurand,A.Zelarayan,L.Betney,R.Gehrke,C.Dunger,S.Noack,C.Busjahn,A.Huelsken,J.Taketo,M.M.Birchmeier,W.Dietz,R.Bergmann,M.W.2007/5/11AdultanalysisAngiotensin IIAnimalsantagonists & inhibitorsbeta CateninCardiomegalyCell MembraneetiologyGene Expression RegulationGenesgeneticsheartHomeostasishypertrophyInsulin-Like Growth Factor Binding Protein 5MiceMice,Inbred C57BLmodelpharmacologyphysiologyProteinsremodelingT-Box Domain ProteinsVentricular RemodelingNot in File13531362Circ.Res.1009Circ.Res.1Sanada2007706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemJournal706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemSanada,S.Hakuno,D.Higgins,L.J.Schreiter,E.R.McKenzie,A.N.Lee,R.T.2007/6/1Angiotensin IIConstrictionfibroblastFibroblastsfibrosisheartheart failurehypertrophyMiceMyocardial InfarctionMyocardiumPhosphorylationPressureResearchsurvivalNot in File15381549J Clin.Invest.1176J Clin.Invest.134-37;39;49;51;58;61;62. Transgenic approaches have not been applied to specifically study the transition from RV hypertrophy to failure. Other important left heart failure models are based on coronary ligation (myocardial infarction) or ischemia/reperfusion ADDIN REFMGR.CITE Orlic2001593Bone marrow cells regenerate infarcted myocardiumJournal593Bone marrow cells regenerate infarcted myocardiumOrlic,D.Kajstura,J.Chimenti,S.Jakoniuk,I.Anderson,S.M.Li,B.Pickel,J.McKay,R.Nadal-Ginard,B.Bodine,D.M.Leri,A.Anversa,P.2001/4/5AnimalsBone Marrow CellsBone Marrow TransplantationCell DifferentiationConnexin 43cytologyDNA-Binding ProteinsFemalegeneticsGreen Fluorescent ProteinsheartKi-67 AntigenLigationLuminescent ProteinsMalemetabolismMiceMice,Inbred C57BLMice,TransgenicMyocardial InfarctionMyocardiumMyogenic Regulatory FactorspathologyProto-Oncogene Proteins c-kitStem CellstherapyTranscription FactorsNot in File701705Nature.4106829Nature.1Edelberg2002587Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heartJournal587Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heartEdelberg,J.M.LEE,S.H.Kaur,M.Tang,L.Feirt,N.M.McCabe,S.Bramwell,O.Wong,S.C.Hong,M.K.2002/2/5Age FactorsAgingAnimalsAnimals,NewbornbiosynthesisCells,CulturedclinicalCoculture TechniquesCoronary VesselscytologyDisease Models,Animaldrug effectsEndothelial CellsEndothelium,VasculargeneticsGraft SurvivalheartHeart TransplantationLigationmetabolismmethodsMiceMice,Inbred C57BLmodelMyocardial InfarctionMyocardiumNeovascularization,PhysiologicpathologyPDGFpharmacologyPhenotypephysiologyPlatelet-Derived Growth Factorprevention & controlProto-Oncogene Proteins c-sisRatsReverse Transcriptase Polymerase Chain ReactiontherapyNot in File608613Circulation.1055Circulation.1Hsieh2006588Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicityJournal588Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicityHsieh,P.C.MacGillivray,C.Gannon,J.Cruz,F.U.Lee,R.T.2006/8/15administration & dosageadverse effectsAnimalschemically inducedDrug Delivery Systemsdrug effectsdrug therapyechocardiographyheartheart failureHemodynamic ProcessesHypertensionHypertension,PulmonaryInjectionsLungMalemethodsMyocardial InfarctionMyocardiumNanotechnologyNOPDGFpharmacologyphysiologyphysiopathologyPlatelet-Derived Growth Factorprevention & controlPulmonary Arterypulmonary hypertensionRandom AllocationRatsRats,Sprague-DawleyRegional Blood FlowsurgerytherapytoxicityVentricular FunctionNot in File637644Circulation.1147Circulation.1Black1998535Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the ratJournal535Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the ratBlack,S.C.Huang,J.Q.Rezaiefar,P.Radinovic,S.Eberhart,A.Nicholson,D.W.Rodger,I.W.1998/4analysisAnimalsapoptosisCaspase 3CaspasesCell DeathCysteineCysteine EndopeptidasescytologyDnaDNA FragmentationenzymologyheartHeart VentriclesischemiaMalemodelMyocardial IschemiaMyocardial ReperfusionMyocardiumpharmacologyphysiopathologyRatsRats,Sprague-DawleyResearchSodiumNot in File733742J.Mol.Cell Cardiol.304J.Mol.Cell Cardiol.1Yaoita1998462Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitorJournal462Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitorYaoita,H.Ogawa,K.Maehara,K.Maruyama,Y.1998/1/27administration & dosageAmino Acid Chloromethyl KetonesAnimalsapoptosiscomplicationsCysteineCysteine EndopeptidasesCysteine Proteinase InhibitorscytologyDisease Models,AnimalDnadrug effectsdrug therapyElectrophoresisElectrophoresis,Agar GeletiologyGenetic TechniquesheartHemodynamic ProcessesLeukocyte CountMalemetabolismmethodsMyocardial InfarctionMyocardial IschemiaMyocardial Reperfusion InjuryMyocardiumpathologypharmacologyphysiopathologyRatsRats,Sprague-DawleyReperfusion InjuryRiskNot in File276281Circulation.973Circulation.1Holly1999463Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivoJournal463Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivoHolly,T.A.Drincic,A.Byun,Y.Nakamura,S.Harris,K.Klocke,F.J.Cryns,V.L.1999/9Amino Acid Chloromethyl KetonesAnimalsapoptosisCaspase 1Caspase 2Caspase 7CaspasesCell DeathCysteine Proteinase InhibitorscytologyEnzyme ActivationenzymologyIn Situ Nick-End LabelingischemiametabolismMyocardial InfarctionMyocardial IschemiaMyocardial ReperfusionMyocardial Reperfusion InjuryMyocardiumpathologypharmacologyPoly(ADP-ribose) PolymerasesRabbitsNot in File17091715J.Mol.Cell Cardiol.319J.Mol.Cell Cardiol.163-68 The relevance of these models to right heart failure associated with PAH is unknown, since it is undetermined whether ischemia plays a role in severe RV pressure overload.
2. Mechanisms of contractile dysfunction in heart failure
Myocyte excitation-contraction coupling
Myocyte excitation-contraction (E-C) coupling involves cytosolic Ca2+ entry through L-type Ca2+ channels (LTCCs); the resultant increase in intracellular Ca2+ triggers further Ca2+ release from the SR through the ryanodine receptor (RyR, see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e1.ppt"fig. e1) ADDIN REFMGR.CITE Bers2002424Cardiac excitation-contraction couplingJournal424Cardiac excitation-contraction couplingBers,D.M.2002/1/10AnimalscalciumCalcium SignalingcytologyheartHumansinnervationmetabolismMuscle RelaxationMyocardial ContractionMyocardiumphysiologyRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumSodiumsympathetic nervous systemNot in File198205Nature.4156868Nature.169. Intracellular Ca2+ binds to troponin C within the myofilaments, which initiates contraction. Subsequent relaxation depends on dissociation of Ca2+ from troponin C and Ca2+ reuptake by the SR through a Ca2+-ATPase (SERCA), interacting with phospholamban ADDIN REFMGR.CITE Schmidt2001425Phospholamban: a promising therapeutic target in heart failure?Journal425Phospholamban: a promising therapeutic target in heart failure?Schmidt,A.G.Edes,I.Kranias,E.G.2001/9AnimalsCalcium-Binding ProteinsCalcium-Transporting ATPasesCardiomyopathiesCardiomyopathy,Dilatedclinicalcontractilitydeficiencyenzymologygeneticsheartheart failureHumansmetabolismMiceMice,KnockoutmodelMyocardial ContractionpharmacologyphysiologyphysiopathologyremodelingreviewSarcoplasmic ReticulumSarcoplasmic Reticulum Calcium-Transporting ATPasesNot in File387396Cardiovasc.Drugs Ther.155Cardiovasc.Drugs Ther.170. Ca2+ is than removed trans-sarcolemmally through the Na/Ca2+ exchanger (NCX) in its forward mode. Unphosphorylated phospholamban inhibits SERCA, and by phosphorylating phospholamban protein kinase A (PKA) enhances SERCA-mediated Ca2+ re-entry into the SR during diastole ADDIN REFMGR.CITE Schmidt2001425Phospholamban: a promising therapeutic target in heart failure?Journal425Phospholamban: a promising therapeutic target in heart failure?Schmidt,A.G.Edes,I.Kranias,E.G.2001/9AnimalsCalcium-Binding ProteinsCalcium-Transporting ATPasesCardiomyopathiesCardiomyopathy,Dilatedclinicalcontractilitydeficiencyenzymologygeneticsheartheart failureHumansmetabolismMiceMice,KnockoutmodelMyocardial ContractionpharmacologyphysiologyphysiopathologyremodelingreviewSarcoplasmic ReticulumSarcoplasmic Reticulum Calcium-Transporting ATPasesNot in File387396Cardiovasc.Drugs Ther.155Cardiovasc.Drugs Ther.170. The efficiency of the trigger (the size of the inward Ca2+ current) needed to cause Ca2+ release from the SR (i.e. the E-C coupling gain, a determinant of contraction velocity) has been shown to be reduced in human heart failure. This can be the result of either functional defects in LTCCs, an increased distance between LTCCs and RyRs, decreased SR Ca2+ stores or functional abnormalities of the RyR ADDIN REFMGR.CITE Yano2005455Altered intracellular Ca2+ handling in heart failureJournal455Altered intracellular Ca2+ handling in heart failureYano,M.Ikeda,Y.Matsuzaki,M.2005/3AnimalscalciumCalcium SignalingCalcium-Binding ProteinsCardiac Output,LowCardiomyopathy,Hypertrophicchemistrycytologygeneticsheartheart failureHumansmetabolismMuscle ProteinsMyocardial ContractionMyocytes,CardiacpathologyphysiologyphysiopathologyRenin-Angiotensin SystemreviewRyanodine Receptor Calcium Release ChannelSarcoplasmic Reticulumsympathetic nervous systemtherapyNot in File556564J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.171. It has also been shown that heart failure is associated with a sustained increase in intracellular Ca2+ concentration, interfering with normal E-C coupling and diastolic relaxation (in addition to inducing maladaptive hypertrophic pathways). Proposed mechanisms are hyperphosphorylation of the RyRs by PKA (while PKA initially improves Ca2+ handling, long-term PKA signaling makes RyRs leaky), decreased SERCA expression/activity and enhanced SERCA inhibition through phospholamban ADDIN REFMGR.CITE Yano2005455Altered intracellular Ca2+ handling in heart failureJournal455Altered intracellular Ca2+ handling in heart failureYano,M.Ikeda,Y.Matsuzaki,M.2005/3AnimalscalciumCalcium SignalingCalcium-Binding ProteinsCardiac Output,LowCardiomyopathy,Hypertrophicchemistrycytologygeneticsheartheart failureHumansmetabolismMuscle ProteinsMyocardial ContractionMyocytes,CardiacpathologyphysiologyphysiopathologyRenin-Angiotensin SystemreviewRyanodine Receptor Calcium Release ChannelSarcoplasmic Reticulumsympathetic nervous systemtherapyNot in File556564J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1Olson2004419A decade of discoveries in cardiac biologyJournal419A decade of discoveries in cardiac biologyOlson,E.N.2004/5AdultAnimalsArrhythmiaCalcium SignalingCardiomegalyCardiomyopathy,Dilatedcongenitalgrowth & developmentheartHeart Conduction SystemHeart Defects,CongenitalHeart DiseaseshistoryHistory,20th CenturyHistory,21st CenturyHumansModels,CardiovascularmortalitypalliationphysiologyReceptors,Adrenergic,betaSignal Transductionstem cell transplantationtherapyNot in File467474Nat.Med.105Nat.Med.1Marx2000457PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing heartsJournal457PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing heartsMarx,S.O.Reiken,S.Hisamatsu,Y.Jayaraman,T.Burkhoff,D.Rosemblit,N.Marks,A.R.2000/5/12AnimalscalciumCardiologyCyclic AMP-Dependent Protein KinasesDogsheartHeart Failure,CongestiveHumansImmunophilinsmetabolismmuscleMyocardiumPhosphorylationRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumSignal TransductionTacrolimus Binding ProteinsNot in File365376Cell.1014Cell.171-73. Heart failure is also associated with an increase in the intracellular Na+ concentration, putting the NCX in its reverse mode and contributing to a further increase in intracellular Ca2+ concentration ADDIN REFMGR.CITE Yano2005455Altered intracellular Ca2+ handling in heart failureJournal455Altered intracellular Ca2+ handling in heart failureYano,M.Ikeda,Y.Matsuzaki,M.2005/3AnimalscalciumCalcium SignalingCalcium-Binding ProteinsCardiac Output,LowCardiomyopathy,Hypertrophicchemistrycytologygeneticsheartheart failureHumansmetabolismMuscle ProteinsMyocardial ContractionMyocytes,CardiacpathologyphysiologyphysiopathologyRenin-Angiotensin SystemreviewRyanodine Receptor Calcium Release ChannelSarcoplasmic Reticulumsympathetic nervous systemtherapyNot in File556564J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.171. The described abnormalities are well established in left heart failure and some of these (decreased expression of mRNAs of SERCA, phospholamban and RyR) have also been shown after PAB in rabbits and rats, without clarification of their consequences for RV systolic function and protein expression ADDIN REFMGR.CITE Matsui1995637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitJournal637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitMatsui,H.MacLennan,D.H.Alpert,N.R.Periasamy,M.1995/1ActinsAnimalsCalcium ChannelsCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCardiomegalycomplicationsdiastolic functionetiologyGene ExpressiongeneticsheartHypertensionhypertrophyMalemetabolismmuscleMuscle ProteinsMyocardiumphysiologyPressureProteinsPulmonary ArteryRabbitsRNA,MessengerRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumNot in FileC252C258Am.J Physiol.2681 Pt 1Am.J Physiol.1LekanneDeprez1998641Changing patterns of gene expression in the pulmonary trunk-banded rat heartJournal641Changing patterns of gene expression in the pulmonary trunk-banded rat heartLekanneDeprez,R.H.van den Hoff,M.J.de Boer,P.A.Ruijter,P.M.Maas,A.A.Chamuleau,R.A.Lamers,W.H.Moorman,A.F.1998/9AmmoniaAnimalsAtrial Natriuretic FactorBiological MarkersbiosynthesisbloodBlotting,NortherncalciumCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCollagenConstrictionCoronary CirculationdiagnosisfibrosisGene Expressiongeneticsheartheart failureHeart Failure,CongestivehypertrophyIn Situ HybridizationLiverMalemetabolismmodelMyocardiumPulmonary ArteryPulmonary CirculationRatsRats,Wistarright ventricleRNA,MessengerStresssurgeryNot in File18771888J Mol.Cell Cardiol.309J Mol.Cell Cardiol.125;26.
Mitochondria, ATP and high energy phosphates
Mitochondria of cardiomyocytes in the failing left heart (there are no data on RV failure in this respect) have structural abnormalities and display reduced activities of electron transport-chain complexes, reduced ATPase synthase capacities and increased levels of uncoupling proteins that cause them to produce heat rather than ATP ADDIN REFMGR.CITE Neubauer2007426The failing heart--an engine out of fuelJournal426The failing heart--an engine out of fuelNeubauer,S.2007/3/15Adenosine TriphosphateAnimalsCreatine Kinasedrug effectsdrug therapyEnergy MetabolismFatty AcidsHeart Failure,CongestiveHumansmetabolismMetabolism,Inborn ErrorsMiceMice,KnockoutMyocardiumOxidation-ReductionOxidative PhosphorylationPeroxisome Proliferator-Activated ReceptorsNot in File11401151N.Engl.J.Med.35611N.Engl.J.Med.174. In advanced heart failure, myocardial ATP levels decrease by 30-40%, but these levels are still well above those required for ATP consuming reactions. A more profound decrease is seen in levels of the high-energy phosphate metabolites creatine and phosphocreatin, contributing to contractile dysfunction when the heart is stressed, such as during the increased sympathetic drive of exercise ADDIN REFMGR.CITE Neubauer2007426The failing heart--an engine out of fuelJournal426The failing heart--an engine out of fuelNeubauer,S.2007/3/15Adenosine TriphosphateAnimalsCreatine Kinasedrug effectsdrug therapyEnergy MetabolismFatty AcidsHeart Failure,CongestiveHumansmetabolismMetabolism,Inborn ErrorsMiceMice,KnockoutMyocardiumOxidation-ReductionOxidative PhosphorylationPeroxisome Proliferator-Activated ReceptorsNot in File11401151N.Engl.J.Med.35611N.Engl.J.Med.174. Concomitantly increased levels of free intracellular ADP further reduce the inotropic reserve. Since there are no known interventions that can directly address these abnormalities, improving myofibrillar efficiency of ATP utilization with calcium-sensitizing drugs is thus far the only possible intervention in this regard ADDIN REFMGR.CITE Ng2004427Levosimendan, a new calcium-sensitizing inotrope for heart failureJournal427Levosimendan, a new calcium-sensitizing inotrope for heart failureNg,T.M.2004/10adverse effectsAnimalscalciumCardiac Output,LowCardiotonic AgentsclinicalClinical Trialsdrug effectsdrug therapyheartheart failureHumansHydrazonesmetabolismmortalityMyocardial ContractionOxygenOxygen ConsumptionpharmacokineticspharmacologyPyridazinestherapeutic usetherapyTreatment OutcometroponinNot in File13661384Pharmacotherapy.2410Pharmacotherapy.175.
Myocardial substrate use
It has been postulated that modification of myocardial substrate use (from fatty acids to glucose) could be used as a strategy to increase the hearts efficiency and lower the oxygen cost of energy generation ADDIN REFMGR.CITE Abozguia2006704Modification of myocardial substrate use as a therapy for heart failureJournal704Modification of myocardial substrate use as a therapy for heart failureAbozguia,K.Clarke,K.Lee,L.Frenneaux,M.2006/9Adrenergic beta-Antagonistsanalogs & derivativesAnimalsCardiac Output,LowCardiovascular Agentsdrug effectsdrug therapyEnergy MetabolismEpoxy CompoundsFatty AcidsFatty Acids,NonesterifiedGlycineheartheart failureHumansmetabolismMyocardiumOxygenPerhexilinepharmacologyPiperazinesPrognosisreviewtherapeutic usetherapyTrimetazidineNot in File490498Nat.Clin.Pract.Cardiovasc.Med.39Nat.Clin.Pract.Cardiovasc.Med.176. This is still a matter of debate, however, since there are inconsistencies in reports on glucose uptake and utilization in heart failure ADDIN REFMGR.CITE Neubauer2007426The failing heart--an engine out of fuelJournal426The failing heart--an engine out of fuelNeubauer,S.2007/3/15Adenosine TriphosphateAnimalsCreatine Kinasedrug effectsdrug therapyEnergy MetabolismFatty AcidsHeart Failure,CongestiveHumansmetabolismMetabolism,Inborn ErrorsMiceMice,KnockoutMyocardiumOxidation-ReductionOxidative PhosphorylationPeroxisome Proliferator-Activated ReceptorsNot in File11401151N.Engl.J.Med.35611N.Engl.J.Med.174. Using [18F]fluorodeoxyglucose positron emission tomography, increased RV glucose utilization was shown in PAH, which was reversed by PGI2 treatment ADDIN REFMGR.CITE Oikawa2005724Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenolJournal724Increased [18F]fluorodeoxyglucose accumulation in right ventricular free wall in patients with pulmonary hypertension and the effect of epoprostenolOikawa,M.Kagaya,Y.Otani,H.Sakuma,M.Demachi,J.Suzuki,J.Takahashi,T.Nawata,J.Ido,T.Watanabe,J.Shirato,K.2005/6/7Antihypertensive AgentsArteriesbrain natriuretic peptidedrug effectsdrug therapyepoprostenolFemaleFluorodeoxyglucose F18Heart VentriclesHumansHypertensionHypertension,PulmonaryMagnetic Resonance ImagingMalemetabolismmethodsMiddle AgedmodelPETpharmacologyphysiopathologyPositron-Emission TomographyPressurePulmonary Arterypulmonary hypertensionStressstroke volumetherapeutic usetherapyVascular ResistanceVentricular PressureNot in File18491855J Am Coll Cardiol.4511J Am Coll Cardiol.177. End-stage heart failure, however, is associated with insulin resistance and decreased glucose uptake and utilization ADDIN REFMGR.CITE Neubauer2007426The failing heart--an engine out of fuelJournal426The failing heart--an engine out of fuelNeubauer,S.2007/3/15Adenosine TriphosphateAnimalsCreatine Kinasedrug effectsdrug therapyEnergy MetabolismFatty AcidsHeart Failure,CongestiveHumansmetabolismMetabolism,Inborn ErrorsMiceMice,KnockoutMyocardiumOxidation-ReductionOxidative PhosphorylationPeroxisome Proliferator-Activated ReceptorsNot in File11401151N.Engl.J.Med.35611N.Engl.J.Med.174. The nuclear receptor p e r o x i s o m e p r o l i f e r a t o r - a c t i v a t e d r e c e p t o r ( P P A R ) p l a y s a n i m p o r t a n t r o l e i n t h e b a l a n c e b e t w e e n l i p i d a n d g l u c o s e m e t a b o l i s m . P P A R r e g u l a t e s t h e e x p r e s s i o n o f g e n e s t h a t e n c o d e p r o t e i n s i n v o l v e d i n t h e u p t a k e a n d - o x i d a t i o n o f f r e e f a t t y a c i d s a n d c e l l u l a r c h o l e s t e r o l t r a f f i c k i n g . P P A R i s d o w n r e g u l a t e d i n h u m a n h e a r t f a i l u r e , b u t t h e c o n s e q u e n c e s o f t h i s a r e c o n t r o v e r s i a l . O n t h e o n e h a n d , a s w i t c h t o g l u c o s e a s a s u b s t r a t e y i e l d s m o r e A T P p e r m o l e c u l e o f o x y g e n , w h i c h c o u l d b e b e n e f i c i a l i n a h y p o x i c h eart ADDIN REFMGR.CITE Schulz2007754PPAR{alpha}: essential component to prevent myocardial oxidative stress?Journal754PPAR{alpha}: essential component to prevent myocardial oxidative stress?Schulz,RichardAli,Mohammad A.M.2007/7/1Oxidative StressStressPPARLipid PeroxidationperoxynitriteSuperoxide DismutaseNot in FileH11H12Am J Physiol Heart Circ Physiol2931http://ajpheart.physiology.orgAJP - Heart and Circulatory Physiology < f n a m e = " S y s t e m " > A m J P h y s i o l H e a r t C i r c P h y s i o l < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 7 8 . O n t h e o t h e r h a n d , d o w n r e g u l a t i o n o f P P A R i s a s s o c i a t e d w i t h a d y s b a l a n c e b e t w e e n r e a c t i v e o x y g e n s p e c i e s (ROS) and antioxidants via decreased superoxide dismutase (SOD) expression ADDIN REFMGR.CITE Guellich2007755Role of oxidative stress in cardiac dysfunction of PPAR{alpha}-/- miceJournal755Role of oxidative stress in cardiac dysfunction of PPAR{alpha}-/- miceGuellich,AzizDamy,ThibaudLecarpentier,YvesConti,MarcClaes,VictorSamuel,Jane LyseQuillard,JeanineHebert,Jean LouisPineau,ThierryCoirault,Catherine2007/7/1analysisdeficiencyechocardiographyGlutathioneMicemuscleNOOxidative StressStressSuperoxide DismutaseNot in FileH93102Am J Physiol Heart Circ Physiol2931http://ajpheart.physiology.org/cgi/content/abstract/293/1/H93AJP - Heart and Circulatory PhysiologyAm J Physiol Heart Circ Physiol179.
3. Causes and consequences of neurohormonal activation and autocrine/paracrine signaling
Reduced tissue perfusion due to a decreased cardiac output activates neurohormonal pathways that are first beneficial (maintenance of blood pressure and renal perfusion), but will eventually decrease cardiac function. Heart failure is associated with upregulation of the renin-angiotensin system (RAS, with ATII as the most important factor involved in cardiac remodeling), adrenergic overstimulation and increased expression of several counter regulating peptides (e.g. natriuretic peptides), all of which have been shown to influence cardiac myocytes, fibroblasts, immune cells and the extracellular matrix. Many of the neurohormones that reach the heart through the systemic circulation are also secreted locally by resident cardiac cells (myocytes, endothelial cells and fibroblasts) and, together with factors that are secreted locally only, affect cardiomyocyte growth, proliferation and survival.
Angiotensin II: primary example of a maladaptive hypertrophic signal
Activation of the RAS involves secretion of renin by juxtaglomerular cells in the kidney in response to reduced perfusion, subsequent renin-induced cleavage of hepatogenic angiotensinogen and production of angiotensin I, and finally conversion of angiotensin I by angiotensin coverting enzyme (ACE) to ATII. The plasma-localized RAS is important in the regulation of salt/water homeostasis and vasoconstriction, regulating blood pressure. ATII can also be produced locally in tissues under different forms of stress, not only by circulating renin and ACE, but also by other enzymes which cleave angiotensinogen and convert angiotensin I ADDIN REFMGR.CITE Kramkowski2006629The physiological significance of the alternative pathways of angiotensin II productionJournal629The physiological significance of the alternative pathways of angiotensin II productionKramkowski,K.Mogielnicki,A.Buczko,W.2006/12Angiotensin IIAngiotensin-Converting Enzyme InhibitorsbiosynthesisbloodChymasesclinicaldrug effectsEnzyme Inhibitorsheartheart failureHumansHypertensionmetabolismpathologyPeptidesPeptidyl-Dipeptidase ApharmacologyphysiologyRenin-Angiotensin SystemreviewNot in File529539J Physiol Pharmacol.574J Physiol Pharmacol.180. Locally produced ATII is involved in tissue remodeling by promoting hyperplasia and hypertrophy of vascular smooth muscle cells, hypertrophic cardiac remodeling and myocardial fibrosis ADDIN REFMGR.CITE Mehta2007411Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular systemJournal411Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular systemMehta,P.K.Griendling,K.K.2007/1Angiotensin IIAnimalsbloodBlood PressureCardiologyCardiovascular DiseasesCardiovascular PhysiologychemistryDisease ProgressionetiologyExtracellular Matrixfibrosisheartheart failureHumansHypertensionhypertrophyinflammationmetabolismmuscleOxygenpathologyphysiologyphysiopathologyreactive oxygen speciesReceptor,Angiotensin,Type 1Receptor,Angiotensin,Type 2Renin-Angiotensin SystemreviewSignal TransductionStructure-Activity RelationshipVascular DiseasesNot in FileC82C97Am.J.Physiol Cell Physiol.2921Am.J.Physiol Cell Physiol.181. Whereas most evidence concerning the role of ATII signaling in pressure overload related heart failure comes from studies on the LV, PAB in rabbits has been shown to cause RV hypertrophy and systolic dysfunction due to signaling defects downstream of ATII (in fact, the density of its receptor, AT1R, was increased) ADDIN REFMGR.CITE Rouleau2001636Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathwayJournal636Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathwayRouleau,J.L.Kapuku,G.Pelletier,S.Gosselin,H.Adam,A.Gagnon,C.Lambert,C.Meloche,S.2001/8/21Angiotensin IIAngiotensin-Converting Enzyme InhibitorsAnimalsantagonists & inhibitorscontractilityDisease Models,AnimalDose-Response Relationship,Drugdrug effectsdrug therapyElectric StimulationGTP-Binding ProteinsheartHemodynamic ProcesseshypertrophyKininsLosartanMalemetabolismmethodsmodelmuscleMyocardial ContractionMyocardiumNOOrgan SizePapillary MusclespathologypharmacologyPhenylephrinephysiopathologyPressureProtein SubunitsPulmonary ArteryRabbitsRamiprilReceptor,Angiotensin,Type 1Receptor,Angiotensin,Type 2Receptors,BradykininReceptors,Angiotensinright ventricleSignal TransductionVentricular Dysfunction,RightVentricular PressureNot in File939944Circulation.1048Circulation.128. Genetic variation in ACE expression has been implicated in the differences in survival between PAH patients ADDIN REFMGR.CITE Abraham1995465Importance of angiotensin-converting enzyme in pulmonary hypertensionJournal465Importance of angiotensin-converting enzyme in pulmonary hypertensionAbraham,W.T.Raynolds,M.V.Gottschall,B.Badesch,D.B.Wynne,K.M.Groves,B.M.Lowes,B.D.Bristow,M.R.Perryman,M.B.Voelkel,N.F.1995Angiotensin IIAnimalscardiac outputCilazaprilDisease Models,Animaldrug effectsdrug therapyElectrophoresis,Agar GelGenotypeHemodynamic ProcessesHumansHypertensionHypertension,PulmonaryhypertrophyLungMalemodelPeptidyl-Dipeptidase AphysiologyphysiopathologyPolymerase Chain ReactionPulmonary Arterypulmonary hypertensionRatsRats,Sprague-Dawleyremodelingright ventricletherapeutic useVascular ResistanceVentricular Dysfunction,RightNot in File915Cardiology.86 (Suppl 1)Cardiology.182.
Most effects of ATII on the heart are mediated by the AT1R, which is a G protein coupled receptor (GPCR). GPCRs are transmembrane receptors with seven domains linked to a guanine nucleotide binding protein (G protein) ADDIN REFMGR.CITE Rockman2002421Seven-transmembrane-spanning receptors and heart functionJournal421Seven-transmembrane-spanning receptors and heart functionRockman,H.A.Koch,W.J.Lefkowitz,R.J.2002/1/10Adrenergic beta-AntagonistsAnimalsbeta-Adrenergic Receptor KinaseCardiovascular DiseaseschemistryCyclic AMP-Dependent Protein KinasesDisease Models,Animaldrug therapyetiologyGTP-Binding ProteinsheartHeart DiseasesHumansmetabolismMicephysiologyProtein ConformationReceptors,AdrenergicReceptors,Cell SurfaceReceptors,MuscarinicSignal Transductiontherapeutic useNot in File206212Nature.4156868Nature.183. GPCR binding with ligand (ATII, catecholamines, ET-1 and others) activates the G protein. Depending on the stimulating ligand and receptor, different downstream effectors are activated, such as phospholipases, adenylate cyclase (AC) and various kinases (see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e2.ppt"fig. e2 and HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%203.ppt"fig. 3). This results in the release of the second messenger molecules such as inositol-1,4,5-triphosphate (IP3), diacylglycerol (DAG) and cyclic adenosine monophosphate (cAMP) ADDIN REFMGR.CITE Rockman2002421Seven-transmembrane-spanning receptors and heart functionJournal421Seven-transmembrane-spanning receptors and heart functionRockman,H.A.Koch,W.J.Lefkowitz,R.J.2002/1/10Adrenergic beta-AntagonistsAnimalsbeta-Adrenergic Receptor KinaseCardiovascular DiseaseschemistryCyclic AMP-Dependent Protein KinasesDisease Models,Animaldrug therapyetiologyGTP-Binding ProteinsheartHeart DiseasesHumansmetabolismMicephysiologyProtein ConformationReceptors,AdrenergicReceptors,Cell SurfaceReceptors,MuscarinicSignal Transductiontherapeutic useNot in File206212Nature.4156868Nature.183. Stimulation of the AT1R is also associated with production of arachidonic acid, linking ATII to inflammatory pathways. Moreover, the AT1R participates in several G-protein independent pathways, including those involving receptor tyrosine kinases (RTKs, e.g. receptors for insulin, epidermal growth factor (EGF), and platelet-derived growth factor (PDGF) ) and non-receptor tyr o s i n e k i n a s e s ( S r c f a m i l y k i n a s e s , J a n u s k i n a s e ( J A K ) ) , p r o v i d i n g a l i n k w i t h s i g n a l i n g t h r o u g h t r a n s f o r m i n g g r o w t h f a c t o r ( T G F ) - 1 , m i t o g e n a c t i v a t e d p r o t e i n k i n a s e s ( M A P K s ) a n d a l d o s t e r o n e . M a n y o f A T I I s e f f e c t s o n t h e h e a r t a n d v a s c u l a t u r e a r e p o t e n t i a t e d b y i n t e r a c t i o n s w i t h T G F - 1 a n d a l d o s t e r o n e , a l t h o u g h t h e u n d e r l y i n g m e c h a n i s m s a r e s t i l l i l l d e f i n e d . O t h e r A T I I m e d i a t e d p a t h o l o g i c e f f e c t s i n t h e v a s c u l a t u r e o c c u r v i a a c t i v a t i o n o f s m a l l G T P b i n d i n g p r o t e i n s , N A D ( P ) H o x i d a s e s a n d s u b s e q u e n t g e n e r a tion of ROS ADDIN REFMGR.CITE Mehta2007411Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular systemJournal411Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular systemMehta,P.K.Griendling,K.K.2007/1Angiotensin IIAnimalsbloodBlood PressureCardiologyCardiovascular DiseasesCardiovascular PhysiologychemistryDisease ProgressionetiologyExtracellular Matrixfibrosisheartheart failureHumansHypertensionhypertrophyinflammationmetabolismmuscleOxygenpathologyphysiologyphysiopathologyreactive oxygen speciesReceptor,Angiotensin,Type 1Receptor,Angiotensin,Type 2Renin-Angiotensin SystemreviewSignal TransductionStructure-Activity RelationshipVascular DiseasesNot in FileC82C97Am.J.Physiol Cell Physiol.2921Am.J.Physiol Cell Physiol.181.
Phospholipase C, protein kinase C, calcineurin
Binding o f A T I I t o t h e A T 1 R ( a n d s i m i l a r l y , E T - 1 o r c a t e c h o l a m i n e s t o t h e i r G P C R ) l e a d s t o p h o s p h o l i p a s e ( P L C ) - a c t i v a t i o n . P L C - r e l e a s e s I P 3 a n d D A G f r o m t h e p l a s m a m e m b r a n e ; I P 3 s u b s e q u e n t l y a c t i v a t e s C a 2 + c h a n n e l s i n t h e S R a n d t h e r e s u l t i n g C a 2 + r e l e a s e i n to the cytoplasm, in conjunction with upregulation of transient receptor potentials (TRCPs), leads to a sustained increase in the intracellular Ca2+ concentration which activates calmodulin and calcineurin phosphatase ADDIN REFMGR.CITE Olson2004419A decade of discoveries in cardiac biologyJournal419A decade of discoveries in cardiac biologyOlson,E.N.2004/5AdultAnimalsArrhythmiaCalcium SignalingCardiomegalyCardiomyopathy,Dilatedcongenitalgrowth & developmentheartHeart Conduction SystemHeart Defects,CongenitalHeart DiseaseshistoryHistory,20th CenturyHistory,21st CenturyHumansModels,CardiovascularmortalitypalliationphysiologyReceptors,Adrenergic,betaSignal Transductionstem cell transplantationtherapyNot in File467474Nat.Med.105Nat.Med.1Ohba2007508Upregulation of TRPC1 in the development of cardiac hypertrophyJournal508Upregulation of TRPC1 in the development of cardiac hypertrophyOhba,T.Watanabe,H.Murakami,M.Takahashi,Y.Iino,K.Kuromitsu,S.Mori,Y.Ono,K.Iijima,T.Ito,H.2007/3Angiotensin IIAtrial Natriuretic Factorbrain natriuretic peptideendothelin-1hearthypertrophyPhenylephrineRatsRnaNot in File498507J.Mol.Cell Cardiol.423J.Mol.Cell Cardiol.1Dorn2005442Protein kinase cascades in the regulation of cardiac hypertrophyJournal442Protein kinase cascades in the regulation of cardiac hypertrophyDorn,G.W.Force,T.2005/31-Phosphatidylinositol 3-KinaseAnimalsbiosynthesiscalciumCardiomegalyenzymologygeneticsGlycogen Synthase KinasesGTP-Binding Protein alpha Subunits,Gq-G11heartHumanshypertrophyIsoenzymesmetabolismmodelMyocardial ContractionMyocardiumpathologyphysiologyphysiopathologyProtein Kinase CProtein KinasesProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktreviewSignal TransductionNot in File527537J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.149;72;84. DAG activates kinases of the PKC family (see below). PLC- / P K C s i g n a l i n g - r e l a t e d h y p e r t r o p h y i s m a i n l y e c c e n t r i c a n d i s a s s o c i a t e d w i t h r e d u c e d c o n t r a c t i l i t y , a d r e n e r g i c d y s f u n c t i o n a n d a p o p t o s i s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > D o r n < / A u t h o r > < Y e a r > 2 0 0 5 < / Y e a r > < R e c N u m > 4 4 2 < / R e c N u m > < I D T e x t > P r o t e i n k i n a s e c a scades in the regulation of cardiac hypertrophyJournal442Protein kinase cascades in the regulation of cardiac hypertrophyDorn,G.W.Force,T.2005/31-Phosphatidylinositol 3-KinaseAnimalsbiosynthesiscalciumCardiomegalyenzymologygeneticsGlycogen Synthase KinasesGTP-Binding Protein alpha Subunits,Gq-G11heartHumanshypertrophyIsoenzymesmetabolismmodelMyocardial ContractionMyocardiumpathologyphysiologyphysiopathologyProtein Kinase CProtein KinasesProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktreviewSignal TransductionNot in File527537J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.184.
In a thus far undetermined way, cardiac myocytes are able to distinguish between the Ca2+ pools involved in contraction and pools involved in transcription-dependent remodeling. It is assumed that Ca2+ compartmentalization and distinct patterns of Ca2+ concentration waveforms trigger specific signal transduction pathways that are otherwise insensitive to the moment-to-moment fluctuations in Ca2+ concentration that are associated with myocyte contraction ADDIN REFMGR.CITE Olson2004419A decade of discoveries in cardiac biologyJournal419A decade of discoveries in cardiac biologyOlson,E.N.2004/5AdultAnimalsArrhythmiaCalcium SignalingCardiomegalyCardiomyopathy,Dilatedcongenitalgrowth & developmentheartHeart Conduction SystemHeart Defects,CongenitalHeart DiseaseshistoryHistory,20th CenturyHistory,21st CenturyHumansModels,CardiovascularmortalitypalliationphysiologyReceptors,Adrenergic,betaSignal Transductionstem cell transplantationtherapyNot in File467474Nat.Med.105Nat.Med.172. After activation by the increase in intracellular Ca2+ concentration, calmodulin activates calcium/calmodulin-dependent protein kinase, which promotes the expression of the transcription factor MEF2 (via nucleo-cytoplasmic transfer of repressing histone deacetylases (HDACs, see below) ADDIN REFMGR.CITE McKinsey2000617Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiationJournal617Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiationMcKinsey,T.A.Zhang,C.L.Lu,J.Olson,E.N.2000/11/2AnimalsBasic Helix-Loop-Helix Transcription FactorsCa(2+)-Calmodulin Dependent Protein KinaseCell DifferentiationCell LineCell NucleusCos CellscytologyDNA-Binding ProteinsgeneticsHistone DeacetylasesHistonesmetabolismmuscleMuscle,SkeletalMutagenesisMyogenic Regulatory FactorsPhosphorylationProtein TransportProteinsRepressor ProteinsSignal TransductionTranscription FactorsNot in File106111Nature.4086808Nature.185. MEF2, mediated by the action of the cytoskeletal protein STARS (striated muscle activator of rho signaling) upregulates the activity of the pro-hypertophic transcription factor SRF (serum response factor) ADDIN REFMGR.CITE Kuwahara2007618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityJournal618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityKuwahara,K.Pipes,G.C.McAnally,J.Richardson,J.A.Hill,J.A.Bassel-Duby,R.Olson,E.N.2007/5CalcineurinCardiomyopathiesCytoskeletal ProteinsCytoskeletonhearthypertrophymodelmusclepathologyPressureProteinsremodelingRhoStressNot in File13241334J.Clin.Invest.1175Journal of Clinical InvestigationJ.Clin.Invest.148. STARS expression is upregulated in human heart failure, and transgenic overexpression of STARS in mice enhances the development of maladaptive hypertrophy and heart failure after TAC ADDIN REFMGR.CITE Zhang2001619Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factorJournal619Cardiomyopathy in transgenic mice with cardiac-specific overexpression of serum response factorZhang,X.Azhar,G.Chai,J.Sheridan,P.Nagano,K.Brown,T.Yang,J.Khrapko,K.Borras,A.M.Lawitts,J.Misra,R.P.Wei,J.Y.2001/4ActinsAgingAnimalsAtrial Natriuretic FactorBlotting,NorthernCardiomyopathiesCollagenDNA-Binding ProteinsDystrophinechocardiographyfibrosisGene Expression Regulation,DevelopmentalGenes,junGenes,fosgeneticsgrowth & developmentheartHumanshypertrophymetabolismMiceMice,TransgenicmuscleMyocardiumMyosin Heavy ChainsNuclear ProteinspathologyphysiologyphysiopathologyProtein IsoformsSerum Response FactorTranscription FactorsVentricular Function,LeftNot in FileH1782H1792Am.J.Physiol Heart Circ.Physiol.2804Am.J.Physiol Heart Circ.Physiol.1Kuwahara2007618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityJournal618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityKuwahara,K.Pipes,G.C.McAnally,J.Richardson,J.A.Hill,J.A.Bassel-Duby,R.Olson,E.N.2007/5CalcineurinCardiomyopathiesCytoskeletal ProteinsCytoskeletonhearthypertrophymodelmusclepathologyPressureProteinsremodelingRhoStressNot in File13241334J.Clin.Invest.1175Journal of Clinical InvestigationJ.Clin.Invest.148;86. Overexpression of SRF without external stimuli is sufficient to cause eccentric hypertrophy and heart failure. In addition to its direct effects on the expression of transcription factors, calmodulin regulates Ca2+ handling and E-C coupling via LTCCs, RyR and SERCA, with a recent report demonstrating early cardiac hypertrophy in mice with impaired calmodulin regulation of RyR2 ADDIN REFMGR.CITE Yamaguchi2007620Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channelJournal620Early cardiac hypertrophy in mice with impaired calmodulin regulation of cardiac muscle Ca release channelYamaguchi,N.Takahashi,N.Xu,L.Smithies,O.Meissner,G.2007/5analysisBody WeightCalcineurinCalmodulinGene ExpressionhearthypertrophyMicemusclepathologyProteinsSarcoplasmic ReticulumNot in File13441353J.Clin.Invest.1175Journal of Clinical InvestigationJ.Clin.Invest.187.
Calcineurin activity is increased in human hearts with compensated hypertrophy, while constitutive activation of calcineurin in transgenic mouse hearts is sufficient to induce massive cardiac enlargement and eventually heart failure ADDIN REFMGR.CITE Molkentin1998418A calcineurin-dependent transcriptional pathway for cardiac hypertrophyJournal418A calcineurin-dependent transcriptional pathway for cardiac hypertrophyMolkentin,J.D.Lu,J.R.Antos,C.L.Markham,B.Richardson,J.Robbins,J.Grant,S.R.Olson,E.N.1998/4/17Angiotensin IIAnimalsAnimals,NewbornAtrial Natriuretic FactorCalcineurinCardiomegalyCell NucleusDNA-Binding ProteinsenzymologyGATA4 Transcription Factorgeneticsheartheart failurehypertrophyImmunosuppressive AgentsmetabolismMiceMice,TransgenicMyocardiumNatriuretic Peptide,BrainNFATC Transcription FactorsNuclear ProteinsoncologypathologypharmacologyPhenylephrinephysiologyprevention & controlPromoter Regions (Genetics)RatsRecombinant Fusion ProteinsSignal TransductionTrans-Activation (Genetics)Transcription FactorsTranscription,GeneticZinc FingersNot in File215228Cell.932Cell.1Haq2001446Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failureJournal446Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failureHaq,S.Choukroun,G.Lim,H.Tymitz,K.M.del,Monte F.Gwathmey,J.Grazette,L.Michael,A.Hajjar,R.Force,T.Molkentin,J.D.2001/2/6Ca(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiologyCardiomegalyCardiomyopathiesdiagnosisenzymologyFemaleGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failureHumanshypertrophyMalemetabolismmethodsMiddle AgedMitogen-Activated Protein Kinase 9Mitogen-Activated Protein Kinasesp38 Mitogen-Activated Protein KinasesProtein KinasesProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktSignal TransductiontherapyNot in File670677Circulation.1035Circulation.188;89. Active calcineurin dephosphorylates the NFAT (nuclear factor of activated T cell) transcription factor, and dephosphorylated NFAT translocates into the nucleus (see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%203.ppt"fig. 3). In the nucleus NFAT activates transcription in cooperation with other transcription factors, including MEF2 and GATA-4 ADDIN REFMGR.CITE McKinsey2005452Toward transcriptional therapies for the failing heart: chemical screens to modulate genesJournal452Toward transcriptional therapies for the failing heart: chemical screens to modulate genesMcKinsey,T.A.Olson,E.N.2005/3Animalsantagonists & inhibitorsCalcineurinCardiac Output,LowcontractilityDNA-Binding ProteinsEnzyme InhibitorsGene ExpressionGene Expression RegulationGene Therapygeneticsheartheart failureHistone DeacetylasesHumanshypertrophymetabolismMyocardiumMyogenic Regulatory FactorsNFATC Transcription FactorsNuclear ProteinspathologyphysiologyphysiopathologyProtein Kinase CremodelingreviewSignal TransductionStresstherapeutic usetherapyTranscription FactorsTranscription,GeneticVentricular RemodelingNot in File538546J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.190. Dephosphorylation of NFAT by calcineurin is inhibited by the transcription factor glycogen synthase kinase-3 (GSK-3, see below) ADDIN REFMGR.CITE Leinwand2001453Calcineurin inhibition and cardiac hypertrophy: a matter of balanceJournal453Calcineurin inhibition and cardiac hypertrophy: a matter of balanceLeinwand,L.A.2001/3/13Adaptor Proteins,Signal TransducingAnimalsantagonists & inhibitorsCalcineurinCardiomegalyCarrier ProteinsCyclosporinedrug therapygeneticsHumanshypertrophyImmunosuppressive AgentsIntracellular Signaling Peptides and ProteinsMuscle ProteinsPhosphoproteinsphysiologyprevention & controlTacrolimustherapeutic useNot in File29472949Proc.Natl.Acad.Sci.U.S.A.986Proc.Natl.Acad.Sci.U.S.A.191. Recently, a family of calcineurin inhibitory proteins termed MCIPs (myocyte-enriched calcineurin-interacting proteins) were identified that seem to function as endogenous modulators of calcineurin activation in the heart ADDIN REFMGR.CITE Frey2003594Cardiac hypertrophy: the good, the bad, and the uglyJournal594Cardiac hypertrophy: the good, the bad, and the uglyFrey,N.Olson,E.N.2003Adaptation,PhysiologicalAnimalsCardiomegalyheartheart failureHumanshypertrophymetabolismmodelMyocardiumphysiologyphysiopathologyreviewStressNot in File4579Annu.Rev.Physiol.65Annu.Rev.Physiol.192. Suppression of calcineurin signaling by either overexpression of MCIP or GSK-3 aborts the hypertrophic response to TAC without affecting LV systolic function ADDIN REFMGR.CITE Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.1Hill2002596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionJournal596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionHill,J.A.Rothermel,B.Yoo,K.D.Cabuay,B.Demetroulis,E.Weiss,R.M.Kutschke,W.Bassel-Duby,R.Williams,R.S.2002/3/22Animalsantagonists & inhibitorsAortaBlood PressureBlotting,NorthernCalcineurinDNA,ComplementaryDose-Response Relationship,DrugechocardiographyElectroencephalographyheartHeart DiseasesHumanshypertrophyMalemetabolismMiceMice,TransgenicMyocardiumpathologyPressureProtein BindingProtein IsoformsRnaRNA,MessengerStressTime FactorsUp-RegulationNot in File1025110255J.Biol.Chem.27712Journal of Biological ChemistryJ.Biol.Chem.137;38. These findings may not be extrapolated to the pressure overloaded RV in PAH without caution. Normal RV afterload and RV wall thickness are only one fifth of that of the LV; the stress imposed by PAH on the RV (doubling or tripling of afterload in comparison with an approximate 50% increase in TAC models) might still require a considerable degree of hypertrophy. There is limited published data available on PKC and calcineurin signaling in the pressure overloaded RV. Braun et al showed that whereas PKC activity was enhanced after PAB in rats, there was no change in expression of calcineurin subunits ADDIN REFMGR.CITE Braun2003646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesJournal646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesBraun,M.U.Szalai,P.Strasser,R.H.Borst,M.M.2003/9/1analogs & derivativesanalysisAngiotensin-Converting Enzyme InhibitorsAnimalsapoptosisbcl-2-Associated X ProteinCalcineurinCardiologyCaspase 3chemistryConstriction,PathologicCytosoldrug therapyenzymologyhypertrophyHypertrophy,Right VentricularImmunoblottingIsoenzymesMalemetabolismmethodsMyocardiumNOpathologypharmacologyPressureProtein Kinase CProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRamiprilRatsRats,WistarremodelingRenin-Angiotensin SystemNot in File658667Cardiovasc.Res.593Cardiovasc.Res.131. Moreover, ACE inhibition did not affect the degree of hypertrophy or PKC upregulation. In another report, PAB was shown to be associated with increased expression of MEF2 and GATA-4 in the RV ADDIN REFMGR.CITE Bar2003644Upregulation of embryonic transcription factors in right ventricular hypertrophyJournal644Upregulation of embryonic transcription factors in right ventricular hypertrophyBar,H.Kreuzer,J.Cojoc,A.Jahn,L.2003/9AdultAnimalsAtrial Natriuretic FactorBasic Helix-Loop-Helix Transcription FactorsBinding SitesBiological MarkersBlotting,WesternCardiologyDisease Models,AnimalDNA-Binding ProteinsGATA4 Transcription FactorGene ExpressionheartHumanshypertrophyHypertrophy,Right VentricularImmunohistochemistryLigationMalemetabolismMicroscopy,FluorescencemodelMyocardiumMyogenic Regulatory FactorsPressureProteinsPulmonary ArteryRatsRats,Sprague-Dawleyright ventricleTranscription FactorsUp-RegulationZebrafish ProteinsNot in File285294Basic Res.Cardiol.985Basic Res.Cardiol.130.
MAPK cascades
Signaling cascades involving MAPKs are recognized as important determinants of the cardiac response to stress. In these cascades, MAPKs are phosphorylated and activated by upstream MAPK kinases (MKKs) which are, in turn, phosphorylated and activated by MKK kinases (MKKKs) ADDIN REFMGR.CITE Sugden1998537"Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardiumJournal537"Stress-responsive" mitogen-activated protein kinases (c-Jun N-terminal kinases and p38 mitogen-activated protein kinases) in the myocardiumSugden,P.H.Clerk,A.1998/8/24AnimalsCa(2+)-Calmodulin Dependent Protein KinaseCardiomegalyEnzyme ActivationenzymologyHumansJNK Mitogen-Activated Protein KinasesMitogen-Activated Protein KinasesMyocardiump38 Mitogen-Activated Protein KinasesphysiologyphysiopathologyProtein KinasesStressSubstrate SpecificityNot in File345352Circ.Res.834Circ.Res.193. In the heart, extracellular signal-regulated kinase ERK1/2 is activated by pro-hypertrophic signals (partly mediated by GPCRs and small GTP binding proteins) ADDIN REFMGR.CITE Bueno2000416The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic miceJournal416The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic miceBueno,O.F.De Windt,L.J.Tymitz,K.M.Witt,S.A.Kimball,T.R.Klevitsky,R.Hewett,T.E.Jones,S.P.Lefer,D.J.Peng,C.F.Kitsis,R.N.Molkentin,J.D.2000/12/1ActininAdenoviridaeAge FactorsAnimalsAnimals,NewbornapoptosisBody WeightCardiomegalyCardiomyopathiesCaspase 3CaspasesCells,CulturedDNA FragmentationDNA,ComplementaryechocardiographyElectrophoresis,Polyacrylamide GelhearthypertrophyImmunohistochemistryIn Situ Nick-End LabelingLeucineMAP Kinase Kinase 1MAP Kinase Signaling SystemmetabolismMiceMice,TransgenicMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein Kinase 8Mitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesMyocardiumOrgan SizePlasmidsProtein-Serine-Threonine KinasesRatsReperfusion InjuryReverse Transcriptase Polymerase Chain ReactionRnaSignal TransductionNot in File63416350EMBO J.1923EMBO J.194, whereas the c-Jun-N-terminal kinases (JNKs) and p38 MAPKs are activated by cellular stress (hypoxia, stretch, oxidative injury) and are associated with cardiac myocyte apoptosis, inflammation and fibrosis (see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e2.ppt"fig. e2) ADDIN REFMGR.CITE Wang1998536Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase familyJournal536Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase familyWang,Y.Huang,S.Sah,V.P.Ross,J.,Jr.Brown,J.H.Han,J.Chien,K.R.1998/1/23AdenoviridaeAnimalsapoptosisAtrial Natriuretic FactorCa(2+)-Calmodulin Dependent Protein KinaseCardiomegalyCell DeathCell SizeCells,Culturedcytologydrug effectsEnzyme ActivationenzymologyGene Transfer Techniquesheartheart failurehypertrophyMAP Kinase Kinase 3MAP Kinase Kinase 6metabolismMiceMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesmuscleMyocardiump38 Mitogen-Activated Protein KinasespathologyProtein-Serine-Threonine KinasesProtein-Tyrosine KinasesSignal TransductionNot in File21612168J.Biol.Chem.2734Journal of Biological ChemistryJ.Biol.Chem.1Liao2001417The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathyJournal417The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathyLiao,P.Georgakopoulos,D.Kovacs,A.Zheng,M.Lerner,D.Pu,H.Saffitz,J.Chien,K.Xiao,R.P.Kass,D.A.Wang,Y.2001/10/9AnimalsCa(2+)-Calmodulin Dependent Protein KinaseCardiomyopathiesCardiomyopathy,RestrictiveCardiotonic AgentsCells,CulturedcytologyenzymologyfibrosisGene ExpressionGene Targetinggeneticsheartheart failureHeart VentriclesHemodynamic ProcessesHumanshypertrophyMAP Kinase Kinase 3MAP Kinase Kinase 6metabolismMiceMice,TransgenicMitogen-Activated Protein Kinase KinasesMitogen-Activated Protein KinasesNOp38 Mitogen-Activated Protein KinasesphysiologyProtein-Tyrosine KinasesRatsremodelingVentricular RemodelingNot in File1228312288Proc.Natl.Acad.Sci.U.S.A.9821Proc.Natl.Acad.Sci.U.S.A.1Tenhunen2006538Identification of cell cycle regulatory and inflammatory genes as predominant targets of p38 mitogen-activated protein kinase in the heartJournal538Identification of cell cycle regulatory and inflammatory genes as predominant targets of p38 mitogen-activated protein kinase in the heartTenhunen,O.Rysa,J.Ilves,M.Soini,Y.Ruskoaho,H.Leskinen,H.2006/9/1AdenoviridaeAdultanalysisAnimalsapoptosisCell CycleCell DivisionCell ProliferationDnaechocardiographyenzymologyfibrosisGene ExpressionGene Expression ProfilingGene Expression Regulation,Enzymologicgene transferGene Transfer TechniquesGenetic VectorsgeneticsheartinflammationIsoenzymesMAP Kinase Kinase 3metabolismMitogen-Activated Protein KinasesMyocardiumOligonucleotide Array Sequence Analysisp38 Mitogen-Activated Protein KinasespathologypharmacologyphysiologyProtein KinasesRatsTranscription FactorsNot in File485493Circ.Res.995Circ.Res.195-97. Overexpression of MAPK phosphatase 1, which inhibits ERK1/2, JNK and p38, prevents both agonist-induced hypertrophy in vitro and pressure overload-associated hypertrophy in vivo, thus demonstrating a significant role for these pathways in hypertrophic signaling ADDIN REFMGR.CITE Bueno2001597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoJournal597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoBueno,O.F.De Windt,L.J.Lim,H.W.Tymitz,K.M.Witt,S.A.Kimball,T.R.Molkentin,J.D.2001/1AdenoviridaeAnimalsAnimals,NewbornAtrial Natriuretic FactorBlotting,WesternCa(2+)-Calmodulin Dependent Protein KinaseCardiomegalyCatecholaminesCells,Culturedchemically inducedcytologyDNA,Recombinantdrug effectsendothelin-1enzymologyFemaleGene Expressiongene transferGene Transfer TechniquesGenetic VectorsgeneticshearthypertrophymetabolismMiceMice,TransgenicMyocardiumNOpharmacologyPhenylephrinePhosphorylationProtein-Tyrosine-PhosphataseRatsRNA,MessengerStressNot in File8896Circ.Res.881Circ.Res.134. Stretched cardiac fibroblasts show integrin-dependent activation of ERK1/2 and JNK ADDIN REFMGR.CITE MacKenna1998397Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblastsJournal397Extracellular signal-regulated kinase and c-Jun NH2-terminal kinase activation by mechanical stretch is integrin-dependent and matrix-specific in rat cardiac fibroblastsMacKenna,D.A.Dolfi,F.Vuori,K.Ruoslahti,E.1998/1/15Ca(2+)-Calmodulin Dependent Protein KinaseJNK Mitogen-Activated Protein KinasesMitogen-Activated Protein Kinase 1Mitogen-Activated Protein KinasesIntegrinsheart failurehypertrophyNot in File301310J.Clin.Invest.1012Journal of Clinical InvestigationJ.Clin.Invest.198. How cell receptors or stress link to the activation of MAPK cascades is not well understood. It is largely undefined which transcription factors MAPKs phosphorylate and what genes are expressed or suppressed as a result of MAPK signaling in the heart, although NFAT and MEF2 have been implicated ADDIN REFMGR.CITE Clerk2006539Inflame my heart (by p38-MAPK)Journal539Inflame my heart (by p38-MAPK)Clerk,A.Sugden,P.H.2006/9/1AnimalsetiologyfibrosisGene ExpressiongeneticsheartHumansMAP Kinase Signaling SystemmetabolismMyocarditisMyocytes,Cardiacp38 Mitogen-Activated Protein KinasespathologyProtein Processing,Post-TranslationalTranscription,GeneticNot in File455458Circ.Res.995Circ.Res.1Frey2003594Cardiac hypertrophy: the good, the bad, and the uglyJournal594Cardiac hypertrophy: the good, the bad, and the uglyFrey,N.Olson,E.N.2003Adaptation,PhysiologicalAnimalsCardiomegalyheartheart failureHumanshypertrophymetabolismmodelMyocardiumphysiologyphysiopathologyreviewStressNot in File4579Annu.Rev.Physiol.65Annu.Rev.Physiol.192;99.
Small GTP binding proteins
This family consists of multiple members, regulating diverse cellular processes such as cell growth, division and survival, organization of the cytoskeleton, membrane trafficking, and cellular motility. Activation of various receptors (GPCRs, RTKs, receptor-independent tyrosine kinases) is associated with the activation of guanine nucleotide exchange factors (GEFs). GEFs mediate substitution of the GDP bound to small GTP binding proteins for GTP. The small GTP binding proteins subsequently acquire GTPase activity and hydrolyze GTP, using the energy to activate various other signaling processes. Five families of small GTP binding proteins have been described (ras, rho, ARFs, rab, ran), each consisting of several members ADDIN REFMGR.CITE Clerk2000598Small guanine nucleotide-binding proteins and myocardial hypertrophyJournal598Small guanine nucleotide-binding proteins and myocardial hypertrophyClerk,A.Sugden,P.H.2000/5/26AnimalsCardiomegalyCytoskeletonetiologyheartheart failureHumanshypertrophyMiceMonomeric GTP-Binding ProteinspathologyphysiologyProtein KinasesProteinsras ProteinsRhorho GTP-Binding ProteinsSignal TransductionTransfectionNot in File10191023Circ.Res.8610Circ.Res.1100. Ras signaling is coupled to multiple downstream effectors involved in the hypertrophic response, including phosphatidylinositol 3-Kinase (PI3K) and MAPKs ADDIN REFMGR.CITE Frey2003594Cardiac hypertrophy: the good, the bad, and the uglyJournal594Cardiac hypertrophy: the good, the bad, and the uglyFrey,N.Olson,E.N.2003Adaptation,PhysiologicalAnimalsCardiomegalyheartheart failureHumanshypertrophymetabolismmodelMyocardiumphysiologyphysiopathologyreviewStressNot in File4579Annu.Rev.Physiol.65Annu.Rev.Physiol.1Clerk2000598Small guanine nucleotide-binding proteins and myocardial hypertrophyJournal598Small guanine nucleotide-binding proteins and myocardial hypertrophyClerk,A.Sugden,P.H.2000/5/26AnimalsCardiomegalyCytoskeletonetiologyheartheart failureHumanshypertrophyMiceMonomeric GTP-Binding ProteinspathologyphysiologyProtein KinasesProteinsras ProteinsRhorho GTP-Binding ProteinsSignal TransductionTransfectionNot in File10191023Circ.Res.8610Circ.Res.192;100. Moreover, activated ras promotes nuclear localization of NFAT, whereas a dominant-negative ras-mutant (N17ras) has been shown to abrogate phenylephrine induced increase in NFAT activity ADDIN REFMGR.CITE Ichida2001599Ras regulates NFAT3 activity in cardiac myocytesJournal599Ras regulates NFAT3 activity in cardiac myocytesIchida,M.Finkel,T.2001/2/2AnimalsCalcineurincyclosporinDNA-Binding ProteinsGTP PhosphohydrolaseshypertrophymetabolismMyocardiumNFATC Transcription FactorsNuclear ProteinsphysiologyProteinsras ProteinsRatsRats,Sprague-DawleySignal TransductionTranscription FactorsTransfectionNot in File35243530J.Biol.Chem.2765Journal of Biological ChemistryJ.Biol.Chem.1101. In the heart, the rho family of small GTP binding proteins (RhoA, Rac, and Cdc42 subfamilies) regulates the cytoskeletal organization of non-muscle cells as well as cardiomyocytes ADDIN REFMGR.CITE Hall1998600Rho GTPases and the actin cytoskeletonJournal600Rho GTPases and the actin cytoskeletonHall,A.1998/1/23ActinsAnimalsCell AdhesionCell CycleCell MovementCytoskeletonEnzyme ActivationEukaryotic CellsGene Expression RegulationGTP PhosphohydrolasesGTP-Binding ProteinsHumansMembrane ProteinsmetabolismphysiologyProteinsResearchRhorhoB GTP-Binding ProteinSignal TransductionultrastructureNot in File509514Science.2795350Science.1Hoshijima1998601The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of Rho kinaseJournal601The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. Involvement of Rho kinaseHoshijima,M.Sah,V.P.Wang,Y.Chien,K.R.Brown,J.H.1998/3/27ADP Ribose TransferasesAnimalsAtrial Natriuretic FactorBotulinum ToxinsCells,Culturedenzymologygene transfergeneticsGTP PhosphohydrolasesGTPase-Activating ProteinshypertrophyIntracellular Signaling Peptides and ProteinsmetabolismmodelMyocardiumMyofibrilsProtein-Serine-Threonine KinasesProteinsras GTPase-Activating ProteinsRatsRats,Sprague-DawleyReceptors,Adrenergic,alpha-1RhoSignal TransductionNot in File77257730J.Biol.Chem.27313Journal of Biological ChemistryJ.Biol.Chem.1102;103. Rho signaling is in many different ways involved in the hypertrophic cardiac response and there are excellent reviews with detailed information ADDIN REFMGR.CITE Brown2006279The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling HitsJournal279The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling HitsBrown,Joan HellerDel Re,Dominic P.Sussman,Mark A.2006/3/31heart failureion channelreactive oxygen speciesRhoNot in File730742Circ Res986http://circres.ahajournals.org/cgi/content/abstract/98/6/730Circ Res1104. To give a few examples, activation of Rho kinase (ROCK) by RhoA is involved in adrenergic and ET-1 induced upregulation of MEF2, SRF and GATA-4 ADDIN REFMGR.CITE Hines1998603Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytesJournal603Ras and rho are required for galphaq-induced hypertrophic gene expression in neonatal rat cardiac myocytesHines,W.A.Thorburn,A.1998/3AnimalsAnimals,Newbornantagonists & inhibitorsAtrial Natriuretic FactorCa(2+)-Calmodulin Dependent Protein KinaseCardiac MyosinsCardiomegalyCells,CulturedEnzyme InhibitorsFlavonoidsGene ExpressiongeneticsGTP-Binding ProteinshypertrophymetabolismMyocardiumMyosin Light ChainspathologypharmacologyPhenotypePhenylephrinePromoter Regions (Genetics)Protein Kinasesras ProteinsRatsRhoRho FactorSignal TransductionTranscription Factor AP-1TransfectionNot in File485494J.Mol.Cell Cardiol.303J.Mol.Cell Cardiol.1Sah1996602Rho is required for Galphaq and alpha1-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathwaysJournal602Rho is required for Galphaq and alpha1-adrenergic receptor signaling in cardiomyocytes. Dissociation of Ras and Rho pathwaysSah,V.P.Hoshijima,M.Chien,K.R.Brown,J.H.1996/12/6ActinsADP Ribose TransferasesAnimalsAntigensAtrial Natriuretic FactorBotulinum ToxinsCa(2+)-Calmodulin Dependent Protein KinaseClostridium botulinumCytosoldrug effectsenzymologyGene ExpressionGene Expression RegulationgeneticsGTP-Binding ProteinshypertrophymetabolismMitogen-Activated Protein Kinase 3Mitogen-Activated Protein KinasesMyocardiumpharmacologyPhenylephrineras ProteinsRatsReceptors,Adrenergic,alpha-1Receptors,Atrial Natriuretic FactorRhoSignal TransductionNot in File3118531190J.Biol.Chem.27149Journal of Biological ChemistryJ.Biol.Chem.1Kuwahara1999604The effects of the selective ROCK inhibitor, Y27632, on ET-1-induced hypertrophic response in neonatal rat cardiac myocytes--possible involvement of Rho/ROCK pathway in cardiac muscle cell hypertrophyJournal604The effects of the selective ROCK inhibitor, Y27632, on ET-1-induced hypertrophic response in neonatal rat cardiac myocytes--possible involvement of Rho/ROCK pathway in cardiac muscle cell hypertrophyKuwahara,K.Saito,Y.Nakagawa,O.Kishimoto,I.Harada,M.Ogawa,E.Miyamoto,Y.Hamanaka,I.Kajiyama,N.Takahashi,N.Izumi,T.Kawakami,R.Tamura,N.Ogawa,Y.Nakao,K.1999/6/11AmidesAnimalsAnimals,Newbornantagonists & inhibitorsAtrial Natriuretic FactorbiosynthesisCell SizeCells,Culturedclinicalcytologydrug effectsendothelin-1Enzyme InhibitorsGene ExpressiongeneticsGTP PhosphohydrolasesheartHumanshypertrophyIntracellular Signaling Peptides and ProteinsKineticsmetabolismmuscleMyocardiumNatriuretic Peptide,BrainpharmacologyProtein-Serine-Threonine KinasesPyridinesRatsRecombinant ProteinsRhoTime FactorsTransfectionNot in File314318FEBS Lett.4523FEBS Lett.1Frey2003594Cardiac hypertrophy: the good, the bad, and the uglyJournal594Cardiac hypertrophy: the good, the bad, and the uglyFrey,N.Olson,E.N.2003Adaptation,PhysiologicalAnimalsCardiomegalyheartheart failureHumanshypertrophymetabolismmodelMyocardiumphysiologyphysiopathologyreviewStressNot in File4579Annu.Rev.Physiol.65Annu.Rev.Physiol.1Chang2005605An expression screen reveals modulators of class II histone deacetylase phosphorylationJournal605An expression screen reveals modulators of class II histone deacetylase phosphorylationChang,ShurongBezprozvannaya,SvetlanaLi,ShijieOlson,Eric N.2005/6/7Binding SitesCos CellsGenomeHistone DeacetylasesPhosphorylationProteinsSerineTranscription FactorsTransfectionNot in File81208125Proc.Natl.Acad.Sci.U.S.A.10223http://www.pnas.org/cgi/content/abstract/102/23/8120Proc.Natl.Acad.Sci.U.S.A.192;105-108. ROCK activation may contribute to hypertrophic sarcomere organization ADDIN REFMGR.CITE Frey2003594Cardiac hypertrophy: the good, the bad, and the uglyJournal594Cardiac hypertrophy: the good, the bad, and the uglyFrey,N.Olson,E.N.2003Adaptation,PhysiologicalAnimalsCardiomegalyheartheart failureHumanshypertrophymetabolismmodelMyocardiumphysiologyphysiopathologyreviewStressNot in File4579Annu.Rev.Physiol.65Annu.Rev.Physiol.192. Two recent reports showed that ROCK and caspase-3 activation are tightly intertwined in causing cardiomyocyte apoptosis, with ROCK acting both up- and downstream of caspase-3 ADDIN REFMGR.CITE Chang2006355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisJournal355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisChang,JiangXie,MinShah,Viraj R.Schneider,Michael D.Entman,Mark L.Wei,LeiSchwartz,Robert J.2006/9/26apoptosisheartheart failuremodelNot in File1449514500Proc.Natl.Acad.Sci.U.S.A.10339http://www.pnas.org/cgi/content/abstract/103/39/14495Proc.Natl.Acad.Sci.U.S.A.1Del Re2007713RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte ApoptosisJournal713RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte ApoptosisDel Re,Dominic P.Miyamoto,ShigekiBrown,Joan Heller2007/3/16apoptosisCaspase 8Caspase 9Cell ProliferationCell SurvivalCytoskeletonDnaDNA FragmentationGene Expressionheartheart failurehypertrophymitochondriaRhosurvivalUp-RegulationNot in File80698078J.Biol.Chem.28211http://www.jbc.org/cgi/content/abstract/282/11/8069Journal of Biological ChemistryJ.Biol.Chem.146;109. A recent study that used targeted deletion of the ROCK-1 isotype in the mouse heart contrasted with many previous studies that relied on pharmacological inhibitors of ROCK. ROCK-1 knock-out in a TAC mouse model did not prevent the development of hypertrophy but rather attenuated the development of cardiac fibrosis ADDIN REFMGR.CITE Zhang2006287Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosisJournal287Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosisZhang,Ying MinBo,JacquelineTaffet,George E.Chang,JiangShi,JianjianReddy,Anilkumar K.Michael,Lloyd H.Schneider,Michael D.Entman,Mark L.Schwartz,Robert J.Wei,Lei2006/5/1myocardial fibrosisheartremodelingRhoNot in File916925FASEB J.207http://www.fasebj.org/cgi/content/abstract/20/7/916The FASEB JournalFASEB J.144. There is strong evidence that ROCK activation also plays a role in the initiation and/or propagation of pulmonary vasoconstriction and vascular remodeling in PAH ADDIN REFMGR.CITE Abe2004244Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in RatsJournal244Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in RatsAbe,KohtaroShimokawa,HiroakiMorikawa,KeikoUwatoku,ToyokazuOi,KeijiMatsumoto,YasuharuHattori,TsuyoshiNakashima,YutakaKaibuchi,KozoSueishi,KatsuoTakeshit,Akira2004/2/20apoptosispulmonary hypertensionRhomonocrotalineNot in File385393Circ Res943http://circres.ahajournals.org/cgi/content/abstract/94/3/385Circ Res1Fagan2004251Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinaseJournal251Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinaseFagan,Karen A.Oka,MasahikoBauer,Natalie R.Gebb,Sarah A.Ivy,D.DunbarMorris,Kenneth G.McMurtry,Ivan F.2004/10/1hypoxiahypoxic pulmonary vasoconstrictionnitric oxidepulmonary hypertensionRhoNot in FileL656L664Am J Physiol Lung Cell Mol Physiol2874http://ajplung.physiology.org/cgi/content/abstract/287/4/L656AJP - Lung Cellular and Molecular PhysiologyAm J Physiol Lung Cell Mol Physiol1Fukumoto2005245Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertensionJournal245Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertensionFukumoto,Y.Matoba,T.Ito,A.Tanaka,H.Kishi,T.Hayashidani,S.Abe,K.Takeshita,A.Shimokawa,H.2005/3/1pulmonary hypertensionRhofasudilNot in File391392Br.Heart J.913http://heart.bmjjournals.comhttp://heart.bmjjournals.com/cgi/reprint/91/3/391HeartBr.Heart J.1Nagaoka2006228Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded ratJournal228Involvement of RhoA/Rho kinase signaling in pulmonary hypertension of the fawn-hooded ratNagaoka,TetsutaroGebb,Sarah A.Karoor,VijayaHomma,NoriyukiMorris,Kenneth G.McMurtry,Ivan F.Oka,Masahiko2006/3/1hypoxiafawn-hooded ratpulmonary hypertensionRhoNot in File9961002J Appl Physiol1003http://jap.physiology.org/cgi/content/abstract/100/3/996Journal of Applied PhysiologyJ Appl Physiol1Abe2006730Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in miceJournal730Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in miceAbe,K.Tawara,S.Oi,K.Hizume,T.Uwatoku,T.Fukumoto,Y.Kaibuchi,K.Shimokawa,H.2006/12ArteriosclerosiseNOSetiologyfasudilHypertensionhypertrophyMicemodelmuscleMuscle Cellsnitric oxideNitric Oxide SynthaseNOPhosphorylationpulmonary hypertensionRatsResearchRhoNot in File280285J Cardiovasc Pharmacol486Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, JapanPM:17204906J Cardiovasc Pharmacol1Ishikura2006227Beneficial Acute Effects of Rho-Kinase Inhibitor in Patients With Pulmonary Arterial HypertensionJournal227Beneficial Acute Effects of Rho-Kinase Inhibitor in Patients With Pulmonary Arterial HypertensionIshikura,KenYamada,NorikazuIto,MasaakiOta,SatoshiNakamura,MashioIsaka,NaokiNakano,Takeshi2006PASMCpulmonary hypertensionRhoNot in File174178Circ J702Circ J13;4;7;110-112.
Aldosterone
As an important mediator of the RAS, aldosterone is best known for its effects on extracellular fluid and potassium homeostasis. The neurohormone is increasingly recognized, however, for its role in the development of heart failure associated with pressure overload and myocardial infarction. Aldosterone has been shown to promote endothelial dysfunction, induce vascular inflammation and myocardial ischemia, increase collagen synthesis in cardiac fibroblasts, increase oxidative stress via NADPH oxidase, and stimulate cardiomyocyte apoptosis ADDIN REFMGR.CITE Cohn2006624Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiologyJournal624Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiologyCohn,J.N.Colucci,W.2006/5/22AldosteroneAldosterone AntagonistsAnimalsapoptosisCardiovascular SystemCollagendrug effectsdrug therapyfibroblastFibroblastsHumansinflammationischemiamodelMyocardial InfarctionMyocardial IschemiaNecrosisNorepinephrineOxidative StressphysiologyphysiopathologyreviewStresstherapeutic useVentricular RemodelingNot in File4F12FAm.J Cardiol.9710AAm.J Cardiol.1113. Likewise, mineralocorticoid receptor (MR) blockade (despite concomitant use of ACE inhibitors or AT1R blockers) is associated with increased nitric oxide (NO) bioavailability, reduced cardiac fibrosis and LV mass, improved LV ejection fraction and diastolic function, and reduced mortality ADDIN REFMGR.CITE Cohn2006624Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiologyJournal624Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiologyCohn,J.N.Colucci,W.2006/5/22AldosteroneAldosterone AntagonistsAnimalsapoptosisCardiovascular SystemCollagendrug effectsdrug therapyfibroblastFibroblastsHumansinflammationischemiamodelMyocardial InfarctionMyocardial IschemiaNecrosisNorepinephrineOxidative StressphysiologyphysiopathologyreviewStresstherapeutic useVentricular RemodelingNot in File4F12FAm.J Cardiol.9710AAm.J Cardiol.1Pitt1999622The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart FailureJournal622The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart FailurePitt,BertramZannad,FaiezRemme,Willem J.Cody,RobertCastaigne,AlainPerez,AlfonsoPalensky,JolieWittes,JanetThe Randomized Aldactone Evaluation Study Investigators,1999/9/2AldosteroneanalysisDigoxinheartheart failureHospitalizationmethodsmortalityNORisktherapyNot in File709717N Engl J Med34110http://content.nejm.org/cgi/content/abstract/341/10/709The New England Journal of MedicineN Engl J Med1Pitt2003623Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial InfarctionJournal623Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial InfarctionPitt,BertramRemme,WillemZannad,FaiezNeaton,JamesMartinez,FelipeRoniker,BarbaraBittman,RichardHurley,SteveKleiman,JayGatlin,Marjoriethe Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators,2003/4/3AldosteroneArrhythmiaheartheart failureHospitalizationmethodsmortalityMyocardial InfarctionRisktherapyNot in File13091321N Engl J Med34814http://content.nejm.org/cgi/content/abstract/348/14/1309The New England Journal of MedicineN Engl J Med1113-115. The underlying signaling mechanisms are not yet fully elucidated. Aldosterone is produced by the adrenals in response to ATII; whether local production in the heart occurs in humans is still a matter of debate ADDIN REFMGR.CITE Cohn2006624Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiologyJournal624Cardiovascular effects of aldosterone and post-acute myocardial infarction pathophysiologyCohn,J.N.Colucci,W.2006/5/22AldosteroneAldosterone AntagonistsAnimalsapoptosisCardiovascular SystemCollagendrug effectsdrug therapyfibroblastFibroblastsHumansinflammationischemiamodelMyocardial InfarctionMyocardial IschemiaNecrosisNorepinephrineOxidative StressphysiologyphysiopathologyreviewStresstherapeutic useVentricular RemodelingNot in File4F12FAm.J Cardiol.9710AAm.J Cardiol.1113. MR binding with aldosterone is associated with ERK1/2 activation, which seems to be mediated by MR induced transactivation of the EGF receptor ADDIN REFMGR.CITE Grossmann2007627Aldosterone-induced Epidermal Growth Factor Receptor (EGFR) expression: Interaction Between the Human Mineralocorticoid Receptor and the Human EGFR PromoterJournal627Aldosterone-induced Epidermal Growth Factor Receptor (EGFR) expression: Interaction Between the Human Mineralocorticoid Receptor and the Human EGFR PromoterGrossmann,C.Krug,A.W.Freudinger,R.Mildenberger,S.Volker,K.Gekle,M.2007/2AldosteroneAortaChromatinDnafibrosismuscleMuscle CellsRatsSpironolactoneNot in FileE1790E1800Am.J Physiol Endocrinol.Metab.2926Am.J Physiol Endocrinol.Metab.1116. The AT1R is capable of a similar transactivation of the EGF receptor (as are other GPCRs), which effect is potentiated by aldosterone ADDIN REFMGR.CITE Mazak2004626Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cellsJournal626Aldosterone potentiates angiotensin II-induced signaling in vascular smooth muscle cellsMazak,I.Fiebeler,A.Muller,D.N.Park,J.K.Shagdarsuren,E.Lindschau,C.Dechend,R.Viedt,C.Pilz,B.Haller,H.Luft,F.C.2004/6/8AldosteroneAldosterone AntagonistsAngiotensin IIAnimalsAnimals,Genetically Modifiedantagonists & inhibitorsCells,Cultureddrug effectsExtracellular Signal-Regulated MAP KinasesJNK Mitogen-Activated Protein KinasesMalemetabolismmethodsmodelmuscleMuscle CellsMuscle,Smooth,VascularOxygenpharmacologyPhosphorylationphysiologyRatsRats,Sprague-Dawleyreactive oxygen speciesReceptor,Epidermal Growth FactorReceptors,MineralocorticoidReninSignal TransductionSpironolactoneNot in File27922800Circulation.10922Circulation.1117.
T r a n s f o r m i n g g r o w t h f a c t o r B e t a 1 ( T G F - 1 )
T G F - 1 i s u p r e g u l a t e d i n t h e h e a r t i n r e s p o n s e t o c h r o n i c p r e s s u r e o v e r l o a d , p r e d o m i n a n t l y m e d i a t e d b y A T I I A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > L i m < / A u t h o r > < Y e a r > 2 0 0 6 < / Y e a r > < R e c N u m > 4 0 9 < / R e c N u m > < I D T e x t > R o l e of transforming growth factor-beta in the progression of heart failureJournal409Role of transforming growth factor-beta in the progression of heart failureLim,H.Zhu,Y.Z.2006/11Angiotensin IIAnimalsCardiac Output,LowChronic DiseaseDisease ProgressionfibrosisheartHeart Diseasesheart failureHumansHypertensionmetabolismmyocardial fibrosisMyocardiumpathologypharmacologySignal TransductionTransforming Growth Factor betaVentricular RemodelingNot in File25842596Cell Mol.Life Sci.6322Cell Mol.Life Sci.1Schneider2002551Serial killer: angiotensin drives cardiac hypertrophy via TGF-beta1Journal551Serial killer: angiotensin drives cardiac hypertrophy via TGF-beta1Schneider,M.D.2002/3Angiotensin IIAnimalsCardiomegalyGene Expression RegulationgeneticsHumanshypertrophymetabolismMyocardiumpathologySignal TransductionTransforming Growth Factor betaTransforming Growth Factor beta1Not in File715716J.Clin.Invest.1096Journal of Clinical InvestigationJ.Clin.Invest.1 < / C i t e > < / R e f m a n > 1 1 8 ; 1 1 9 . I n f a c t , m a n y o f A T I I s e f f e c t s o n v e n t r i c u l a r m a s s , c a r d i o m y o c y t e s i z e , a n d c o n t r a c t i l i t y a r e m e d i a t e d b y T G F - 1 A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > S c h u l t z < / A u t h o r > < Y e a r > 2 0 0 2 < / Y e a r > < R e c N u m > 5 5 0 < / R e c N u m > < I D T e x t > T G F - b e t a 1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin IIJournal550TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin IISchultz,Jel J.Witt,S.A.Glascock,B.J.Nieman,M.L.Reiser,P.J.Nix,S.L.Kimball,T.R.Doetschman,T.2002/3analysisAngiotensin IIAnimalsAtrial Natriuretic FactorCardiomegalyCell Sizecytologydrug effectsechocardiographyfibrosisGene ExpressiongeneticsheartHemodynamic ProcesseshypertrophymetabolismMiceMice,Inbred StrainsMice,KnockoutMyocardiumMyosin Heavy ChainsNOpathologypharmacologyphysiologyphysiopathologyTransforming Growth Factor betaTransforming Growth Factor beta1Not in File787796J.Clin.Invest.1096Journal of Clinical InvestigationJ.Clin.Invest.1120 . M o s t c a r d i a c T G F - 1 m R N A c a n b e f o u n d i n c a r d i a c f i b r o b l a s t s , w h i c h i s r e f l e c t e d i n t h e a s s o c i a t i o n o f T G F - 1 a c t i v a t i o n w i t h i n c r e a s e d m y o c a r d i a l f i b r o s i s a n d t h e p r o g r e s s i o n t o s y s t o l i c a n d d i a s t o l i c h e a r t f a i l u r e d u r i n g c h r o n i c p r e s s u r e o v e r l o a d A D D IN REFMGR.CITE Lim2006409Role of transforming growth factor-beta in the progression of heart failureJournal409Role of transforming growth factor-beta in the progression of heart failureLim,H.Zhu,Y.Z.2006/11Angiotensin IIAnimalsCardiac Output,LowChronic DiseaseDisease ProgressionfibrosisheartHeart Diseasesheart failureHumansHypertensionmetabolismmyocardial fibrosisMyocardiumpathologypharmacologySignal TransductionTransforming Growth Factor betaVentricular RemodelingNot in File25842596Cell Mol.Life Sci.6322Cell Mol.Life Sci.1118 . A f t e r e x c r e t i o n , T G F - 1 b i n d s t o a d i m e r i z e d c o m p l e x o f t w o s e r i n e - t h r e o n i n e k i n a s e r e c e p t o r s ( T G F - 1 r e c e p t o r s 1 a n d 2 ) a n d s u b s e q u e n t s i g n a l i n g i s r e a l i z e d v i a t w o d i f f e r e n t p a t h w a y s : p h o s p h o r y l a t i o n o f S m a d p r o t e i n s a n d a c t i v a t i o n o f T G F - - a c t i v a t e d k inase (TAK)1 ADDIN REFMGR.CITE Khan2006410Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmiaJournal410Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmiaKhan,R.Sheppard,R.2006/5antagonists & inhibitorsArrhythmiaCardiomyopathiesCytokinesfibroblastFibroblastsfibrosisheartHeart DiseasesHeart Valve DiseasesHumansMatrix MetalloproteinasesmetabolismMyocardial InfarctionMyocardiumpathologyphysiologyphysiopathologyreviewtherapyTransforming Growth Factor betaTransforming Growth Factor beta1Not in File1024Immunology.1181 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > I m m u n o l o g y . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 2 1 . T h e T G F - 1 S m a d p a t h w a y a p p e a r s t o b e i n v o l v e d i n t h e a c t i v a t i o n o f c o l l a g e n - g e n e p r o m o t e r s i t e s , p r i m a r i l y e n h ancing DNA translation of collagen type I ADDIN REFMGR.CITE Khan2006410Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmiaJournal410Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmiaKhan,R.Sheppard,R.2006/5antagonists & inhibitorsArrhythmiaCardiomyopathiesCytokinesfibroblastFibroblastsfibrosisheartHeart DiseasesHeart Valve DiseasesHumansMatrix MetalloproteinasesmetabolismMyocardial InfarctionMyocardiumpathologyphysiologyphysiopathologyreviewtherapyTransforming Growth Factor betaTransforming Growth Factor beta1Not in File1024Immunology. < V o l u m e > 1 1 8 < / V o l u m e > < I s s u e > 1 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > I m m u n o l o g y . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 2 1 . T A K 1 i s a M K K K f a m i l y m e m b e r a n d l i n k s T G F - 1 t o t h e M A P K s p 3 8 a n d J N K A D D I N R E F M GR.CITE Zhang2000552TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic miceJournal552TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic miceZhang,D.Gaussin,V.Taffet,G.E.Belaguli,N.S.Yamada,M.Schwartz,R.J.Michael,L.H.Overbeek,P.A.Schneider,M.D.2000/5Activating Transcription Factor 6AdultAnimalsAortaapoptosisbiosynthesisBlood PressureCardiac Output,LowCardiomegalyDiastoleDNA-Binding ProteinsDown-Regulationetiologyfibrosisgeneticsheartheart failurehypertrophyMaleMAP Kinase Kinase KinasesmetabolismMiceMice,Inbred C57BLMice,TransgenicMitogen-Activated Protein KinasesMutationMyocardiumNuclear Proteinsp38 Mitogen-Activated Protein KinasesPhosphorylationSerum Response FactorSignal TransductionStresssurgerySystoleTranscription FactorsTransforming Growth Factor betaNot in File556563Nat.Med.65Nat.Med.1122. TAK1 is expressed at low levels in the normal adult heart, but transgenic constitutive activation of TAK1 in the myocardium without overload is sufficient to reproduce the full histological picture of heart failure, including hypertrophied cardiomyocytes, fetal gene re-expression, cardiomyocyte drop-out (with high rates of apoptosis) and interstitial fibrosis ADDIN REFMGR.CITE Zhang2000552TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic miceJournal552TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic miceZhang,D.Gaussin,V.Taffet,G.E.Belaguli,N.S.Yamada,M.Schwartz,R.J.Michael,L.H.Overbeek,P.A.Schneider,M.D.2000/5Activating Transcription Factor 6AdultAnimalsAortaapoptosisbiosynthesisBlood PressureCardiac Output,LowCardiomegalyDiastoleDNA-Binding ProteinsDown-Regulationetiologyfibrosisgeneticsheartheart failurehypertrophyMaleMAP Kinase Kinase KinasesmetabolismMiceMice,Inbred C57BLMice,TransgenicMitogen-Activated Protein KinasesMutationMyocardiumNuclear Proteinsp38 Mitogen-Activated Protein KinasesPhosphorylationSerum Response FactorSignal TransductionStresssurgerySystoleTranscription FactorsTransforming Growth Factor betaNot in File556563 N a t . M e d . < / P e r i o d i c a l > < V o l u m e > 6 < / V o l u m e > < I s s u e > 5 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > N a t . M e d . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 2 2 . T A K 1 c a n a l s o b e a c t i v a t e d b y o t h e r c y t o k i n e s t h a n T G F - 1 , i n c l u d i n g t u m o r n e c r o s i s f a c t o r ( T N F ) a n d i n t e r l e u k i n ( I L ) - 1 A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > N i n o m i y a - T s u j i < / A u t h o r > < Y e a r > 1 9 9 9 < / Y e a r > < R e c N u m > 5 5 3 < / R e c N u m > < I D T e x t > T h e k i n a s e T A K 1 c a n a c t i v a t e t h e N I K - I k a p p a B a s w e l l a s t h e M A P k i n a s e c a s c a d e i n the IL-1 signalling pathwayJournal553The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathwayNinomiya-Tsuji,J.Kishimoto,K.Hiyama,A.Inoue,J.Cao,Z.Matsumoto,K.1999/3/18Ca(2+)-Calmodulin Dependent Protein KinaseCell LineEnzyme ActivationgeneticsI-kappa B KinaseinflammationInterleukin-1JNK Mitogen-Activated Protein KinasesMAP Kinase Kinase KinasesmetabolismMitogen-Activated Protein KinasesMultienzyme ComplexesMutagenesisNF-kappa BPhosphorylationPrecipitin TestsProtein-Serine-Threonine KinasesProteinsRecombinant Fusion ProteinsSerineSignal TransductionThreonineTNF Receptor-Associated Factor 6TransfectionNot in File252256Nature.3986724Nature.1123.
Catecholamines
The effect of interaction of adrenergic agonists (adrenalin and noradrenalin) with their GPCR is dependent on the adrenergic receptor subtype. Upon receptor bin d i n g , A C i s a c t i v a t e d a n d c A M P i s p r o d u c e d ( 1 a n d 2 r e c e p t o r s ) , P I 3 K i s a c t i v a t e d ( 2 r e c e p t o r s ) , M A P K s a r e a c t i v a t e d ( 2 a n d 1 r e c e p t o r s ) a n d I P 3 a n d D A G a r e p r o d u c e d ( 1 r e c e p t o r ) A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > R o c k m a n < / A u t h o r > < Y e a r > 2 0 0 2 < / Y ear>421Seven-transmembrane-spanning receptors and heart functionJournal421Seven-transmembrane-spanning receptors and heart functionRockman,H.A.Koch,W.J.Lefkowitz,R.J.2002/1/10Adrenergic beta-AntagonistsAnimalsbeta-Adrenergic Receptor KinaseCardiovascular DiseaseschemistryCyclic AMP-Dependent Protein KinasesDisease Models,Animaldrug therapyetiologyGTP-Binding ProteinsheartHeart DiseasesHumansmetabolismMicephysiologyProtein ConformationReceptors,AdrenergicReceptors,Cell SurfaceReceptors,MuscarinicSignal Transductiontherapeutic useNot in File206212Nature.4156868Nature.183. There are a number of ways in which adrenergic stimulation contributes to hypertrophy and, after prolonged simulation, to cardiac dysfunction. Production of cAMP leads to the activation of PKA, which initially improves Ca2+ handling (phosphorylation of phospholamban increases Ca2+ reuptake by the SR through SERCA). Long-term PKA signaling, however, leads to hyperphosphorylation of RyRs and a sustained increase in intracellular Ca2+ and maladaptive hypertrophy. PKA phosphorylates the transcription factor CREB (cAMP-response element binding protein), which has also been suggested to contribute to the development of ventricular dilatation and failure ADDIN REFMGR.CITE Fentzke1998693Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heartJournal693Dilated cardiomyopathy in transgenic mice expressing a dominant-negative CREB transcription factor in the heartFentzke,R.C.Korcarz,C.E.Lang,R.M.Lin,H.Leiden,J.M.1998/6/1AnimalsapoptosisCardiomyopathiesCardiomyopathy,DilatedclinicalCyclic AMP Response Element-Binding ProteinechocardiographyetiologyfibrosisGene Expression RegulationgeneticsheartHeart Failure,CongestiveIsoproterenolMalemetabolismMiceMice,TransgenicmodelmortalityMyocardiumMyosin Heavy ChainspathologyphysiologytherapyVentricular FunctionVentricular Function,LeftNot in File24152426J Clin.Invest.10111J Clin.Invest.1124. Phosphorylated CREB interacts with CREB binding protein and p300, a histone acetyltransferase (HAT), to induce relaxation of the chromatin structure and promote gene activation (see below) ADDIN REFMGR.CITE Backs2006694Control of cardiac growth by histone acetylation/deacetylationJournal694Control of cardiac growth by histone acetylation/deacetylationBacks,J.Olson,E.N.2006/1/6AcetylationAnimalsCardiomegalyChromatinDnaetiologyGene Expressiongrowth & developmentheartheart failureHistone AcetyltransferasesHistone DeacetylasesHistonesHumansMADS Domain ProteinsmetabolismMyogenic Regulatory FactorsphysiologyProtein Kinase CProtein Processing,Post-TranslationalremodelingSignal TransductionStressTranscription FactorsTranscription,GeneticNot in File1524Circ.Res.981Circ.Res.1125. It was recently shown that cAMP may also affect cardiomyocyte calcium handling through PKA independent mechanisms, such as activation of epac (exchange protein activated by cAMP) and, subsequently, Ca2+-calmodulin dependent protein kinase II (CaMKII) ADDIN REFMGR.CITE Pereira2007767The cAMP binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat cardiac myocytesJournal767The cAMP binding protein Epac modulates Ca2+ sparks by a Ca2+/calmodulin kinase signalling pathway in rat cardiac myocytesPereira,LaetitiaMetrich,MelanieFernandez-Velasco,MariaLucas,AlexandreLeroy,JeromePerrier,RomainMorel,EricFischmeister,RodolpheRichard,SylvainBenitah,Jean PierreLezoualc'h,FrankGomez,Ana Maria2007/9/1AdultcalciumPhosphorylationSarcoplasmic ReticulumNot in File685694J Physiol (Lond)5832http://jp.physoc.org/cgi/content/abstract/583/2/685The Journal of Physiology OnlineJ Physiol (Lond)1126.
Chronically increased levels of circulating catecho l a m i n e s , s u c h a s i n h u m a n h e a r t f a i l u r e , a r e a s s o c i a t e d w i t h a d e c r e a s e i n - A R d e n s i t y A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > R o c k m a n < / A u t h o r > < Y e a r > 2 0 0 2 < / Y e a r > < R e c N u m > 4 2 1 < / R e c N u m > < I D T e x t > S e v e n - t r a n s m e m b r a n e - s p a n n i n g r e c e p t o r s a n d h e a r t f u n c t i o n < / I D T e x t >Journal421Seven-transmembrane-spanning receptors and heart functionRockman,H.A.Koch,W.J.Lefkowitz,R.J.2002/1/10Adrenergic beta-AntagonistsAnimalsbeta-Adrenergic Receptor KinaseCardiovascular DiseaseschemistryCyclic AMP-Dependent Protein KinasesDisease Models,Animaldrug therapyetiologyGTP-Binding ProteinsheartHeart DiseasesHumansmetabolismMicephysiologyProtein ConformationReceptors,AdrenergicReceptors,Cell SurfaceReceptors,MuscarinicSignal Transductiontherapeutic useNot in File206212Nature.4156868Nature.183 and a PI3K (subtype p 1 1 0 ) m e d i a t e d i n c r e a s e i n t h e e x p r e s s i o n o f - A R k i n a s e ( - A R K ) , w h i c h i s a k i n a s e t h a t p h o s p h o r y l a t e s t h e c y t o p l a s m i c t a i l o f t h e r e c e p t o r a n d d e c r e a s e s i t s s e n s i t i v i t y A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > P e r r i n o < / A u t h o r > < Y e a r > 2 0 0 6 < / Y e a r > < R e c N u m > 470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionJournal470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionPerrino,C.Naga Prasad,S.V.Mao,L.Noma,T.Yan,Z.Kim,H.S.Smithies,O.Rockman,H.A.2006/61-Phosphatidylinositol 3-KinaseAdrenergic beta-AntagonistsAnimalsantagonists & inhibitorsbeta-Adrenergic Receptor KinaseBlood PressureBlood VesselsCardiac Output,LowCardiomegalyCells,CulturedcytologyechocardiographyexerciseFemaleGene ExpressionGene Expression RegulationgeneticsheartHemodynamic ProcessesHumansHypertensionhypertrophyHypertrophy,Left VentricularmetabolismMetoprololMiceMice,Inbred C57BLMice,TransgenicMyocardiumpathologyPhenotypephysiologyphysiopathologyReceptors,Adrenergic,betaSignal TransductionStressNot in File15471560J.Clin.Invest.1166Journal of Clinical InvestigationJ.Clin.Invest.143 . E x p r e s s i o n o f a d o m i n a n t n e g a t i v e - A R K m u t a n t p r e v e n t s p a t h o l o g i c a l h y p e r t r o p h y a n d h e a r t f a i l u r e i n m i c e c h r o n i c a l l y i n f u s e d w i t h i s o p r o t e r e n o l A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > K o c h < / A u t h o r > < Y e a r > 1 9 9 5 < / Y e a r > < R e c N u m > 4 2 2 < / R e c N u m > < I D T e x t > C a r d i a c function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitorJournal422Cardiac function in mice overexpressing the beta-adrenergic receptor kinase or a beta ARK inhibitorKoch,W.J.Rockman,H.A.Samama,P.Hamilton,R.A.Bond,R.A.Milano,C.A.Lefkowitz,R.J.1995/6/2Adenylate CyclaseAnimalsantagonists & inhibitorsbeta-Adrenergic Receptor KinaseBlood PressurecontractilityCyclic AMP-Dependent Protein Kinasesdrug effectsenzymologygeneticsGTP-Binding Proteinsheartheart failureIsoproterenolmetabolismMiceMice,TransgenicmodelMyocardial ContractionMyocardiumpharmacologyPhenotypephysiologyReceptors,Adrenergic,betaSarcolemmaVentricular PressureNot in File13501353Science.2685215Science.161 and in rabbits subjected to PAB ADDIN REFMGR.CITE Emani2001638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingJournal638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingEmani,S.M.Shah,A.S.White,D.C.Glower,D.D.Koch,W.J.2001/11Animalsbeta-Adrenergic Receptor Kinasebeta-GalactosidaseCarrier ProteinsclinicalGene Therapygene transferHeart VentricleshypertrophymethodsmortalitypathologyPeptidesPressurePulmonary ArteryRabbitsRecombinant ProteinssurgerysurvivalSurvival Ratetherapeutic usetherapyTransgenesVentricular Dysfunction,RightVentricular PressureNot in File16571661Ann.Thorac.Surg.725Ann.Thorac.Surg.129. This seems paradoxal in the light of the clinical findin g t h a t b l o c k i n g t h e - A R i n p a t i e n t s w i t h h e a r t f a i l u r e i m p r o v e s s u r v i v a l a n d p r e v e n t s p a t h o l o g i c a l r e m o d e l i n g A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > B r i s t o w < / A u t h o r > < Y e a r > 2 0 0 3 < / Y e a r > < R e c N u m > 4 2 3 < / R e c N u m > < I D T e x t > A n t i a d r e n e r g i c t h e r a p y o f c h r o n i c h e a r t f a ilure: surprises and new opportunitiesJournal423Antiadrenergic therapy of chronic heart failure: surprises and new opportunitiesBristow,M.2003/3/4Adrenergic beta-Antagonistsadverse effectsChronic DiseaseClinical Trialsdrug therapygeneticsheartheart failureHeart Failure,CongestiveHumansPolymorphism,GeneticReceptors,AdrenergicSympatholyticstherapeutic usetherapyNot in File11001102Circulation.1078 C i r c u l a t i o n . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 2 7 . T h e c o n s e q u e n c e s o f P L C - a n d M A P K s a c t i v a t i o n b y c h r o n i c a d r e n e r g i c s t i m u l a t i o n w e r e d i s c u s s e d a b o v e . F i n a l l y , p r e s s u r e o v e r l o a d i n t h e M C T m o del is associated with RV specific anatomical sympathetic hyperinnervation, which is due to upregulation of cardiomyocyte-derived neuronal growth factor (NGF) ADDIN REFMGR.CITE Kimura2007742Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac HypertrophyJournal742Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac HypertrophyKimura,KensukeIeda,MasakiKanazawa,HideakiYagi,TakashiTsunoda,MakotoNinomiya,Shin ichiKurosawa,HiroyukiYoshimi,KenjiMochizuki,HidekiYamazaki,KazutoOgawa,SatoshiFukuda,Keiichi2007/6/22Angiotensin IIendothelin-1hearthypertrophyinnervationmonocrotalineNorepinephrinepulmonary hypertensionRatsright ventricleNot in File17551764Circ Res10012http://circres.ahajournals.org/cgi/content/abstract/100/12/1755Circ Res112. The newly developed neurons have embryonic characteristics and are functionally inferior to mature neurons. Upregulation of NGF in the MCT model likely results from ET-1 signaling ADDIN REFMGR.CITE Ieda2004743Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expressionJournal743Endothelin-1 regulates cardiac sympathetic innervation in the rodent heart by controlling nerve growth factor expressionIeda,MasakiFukuda,KeiichiHisaka,YasuyoKimura,KensukeKawaguchi,HarukoFujita,JunShimoda,KoujiTakeshita,EikoOkano,HideyukiKurihara,YukikoKurihara,HirokiIshida,JunjiFukamizu,AkiyoshiFederoff,Howard J.Ogawa,Satoshi2004/3/15apoptosisendothelin-1heartinnervationMiceNerve growth factorNorepinephrineNot in File876884J.Clin.Invest.1136http://www.jci.org/cgi/content/abstract/113/6/876Journal of Clinical InvestigationJ.Clin.Invest.1128.
Endothelin-1
In addition to its vasoactive effects, ET-1 regulates a variety of biological processes in non-vascular tissues. ET-1 augments cardiomyocyte contractility and plays a role in the development of pressure overload induced cardiac hypertrophy ADDIN REFMGR.CITE Sugden2003663An overview of endothelin signaling in the cardiac myocyteJournal663An overview of endothelin signaling in the cardiac myocyteSugden,P.H.2003/8Animalsapoptosiscalciumdrug effectsEndothelinsEnzyme ActivationHumansHydrolysismetabolismMitogen-Activated Protein KinasesModels,BiologicalMyocytes,CardiacpharmacologyProtein IsoformsProtein Kinase CProtein KinasesSignal TransductionSodiumTranscription FactorsTranscription,GeneticNot in File871886J Mol.Cell Cardiol.358J Mol.Cell Cardiol.1Giannessi2001670The role of endothelins and their receptors in heart failureJournal670The role of endothelins and their receptors in heart failureGiannessi,D.Del,Ry S.Vitale,R.L.2001/2abnormalitiesAmino AcidsAnimalsantagonists & inhibitorsbloodBlood PressureCardiomegalyclinicalCytokinesdrug effectsdrug therapyEmbryoEndothelial Cellsendothelin-1Endothelin-2Endothelin-3EndothelinsEnzyme Inhibitorsheartheart failureHeart Failure,CongestiveHomeostasisHumansmetabolismmodelpharmacologyphysiologyPressureReceptors,EndothelinSignal Transductiontherapeutic useVasoconstrictionVentricular RemodelingNot in File111126Pharmacol.Res.432Pharmacol.Res.1129;130. ET-1 can induce mast cell degranulation and subsequent activation of matrix metalloproteinases (MMPs) ADDIN REFMGR.CITE Murray2004505Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in ratsJournal505Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in ratsMurray,D.B.Gardner,J.D.Brower,G.L.Janicki,J.S.2004/11AnimalsbloodCell DegranulationCollagendrug effectsendothelin-1Enzyme ActivationenzymologyheartMaleMast CellsMatrix MetalloproteinasesmetabolismMyocardiumpharmacologyphysiologyRatsRats,Sprague-DawleyremodelingVentricular RemodelingNot in FileH2295H2299Am.J.Physiol Heart Circ.Physiol.2875Am.J.Physiol Heart Circ.Physiol.1131. In PAH and heart failure, ET-1 serum concentrations are elevated, due to increased production by endothelial cells and cardiomyocytes in response to various stimuli (e.g. vasoactive hormones, growth factors, shear stress, hypoxia, ROS) ADDIN REFMGR.CITE Giannessi2001670The role of endothelins and their receptors in heart failureJournal670The role of endothelins and their receptors in heart failureGiannessi,D.Del,Ry S.Vitale,R.L.2001/2abnormalitiesAmino AcidsAnimalsantagonists & inhibitorsbloodBlood PressureCardiomegalyclinicalCytokinesdrug effectsdrug therapyEmbryoEndothelial Cellsendothelin-1Endothelin-2Endothelin-3EndothelinsEnzyme Inhibitorsheartheart failureHeart Failure,CongestiveHomeostasisHumansmetabolismmodelpharmacologyphysiologyPressureReceptors,EndothelinSignal Transductiontherapeutic useVasoconstrictionVentricular RemodelingNot in File111126Pharmacol.Res.432Pharmacol.Res.1Cody1992669Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failureJournal669Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failureCody,R.J.Haas,G.J.Binkley,P.F.Capers,Q.Kelley,R.1992/2AdultAgedanalysisbloodChronic Diseasecomplicationsendothelin-1EndothelinsetiologyFemaleheartheart failureHeart Failure,CongestiveHemodynamic ProcessesHumansHypertensionHypertension,PulmonaryMalemethodsMiddle AgedPeptidesphysiopathologyPressurepulmonary hypertensionPulmonary Wedge PressureRadioimmunoassayRegression AnalysisVascular ResistanceVasoconstrictionNot in File504509Circulation.852Circulation.1Sakai1996668Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heartJournal668Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heartSakai,S.Miyauchi,T.Sakurai,T.Kasuya,Y.Ihara,M.Yamaguchi,I.Goto,K.Sugishita,Y.1996/3/15analysisAnimalsbloodBlood Pressureclinicalcontractilityendothelin-1Endothelinsetiologygeneticsheartheart failureHeart Failure,Congestiveheart rateHemodynamic ProcessesMalemethodsmodelPeptides,CyclicpharmacologyphysiologyphysiopathologyPressureProtein PrecursorsRatsRats,Sprague-DawleyReninRNA,MessengerSignal TransductionsurgeryNot in File12141222Circulation.936Circulation.1130;132;133. ET-1 production is inhibited by cGMP, either produced in response to NO or natriuretic peptides ADDIN REFMGR.CITE Giannessi2001670The role of endothelins and their receptors in heart failureJournal670The role of endothelins and their receptors in heart failureGiannessi,D.Del,Ry S.Vitale,R.L.2001/2abnormalitiesAmino AcidsAnimalsantagonists & inhibitorsbloodBlood PressureCardiomegalyclinicalCytokinesdrug effectsdrug therapyEmbryoEndothelial Cellsendothelin-1Endothelin-2Endothelin-3EndothelinsEnzyme Inhibitorsheartheart failureHeart Failure,CongestiveHomeostasisHumansmetabolismmodelpharmacologyphysiologyPressureReceptors,EndothelinSignal Transductiontherapeutic useVasoconstrictionVentricular RemodelingNot in File111126Pharmacol.Res.432Pharmacol.Res.1130.
ET-1 exerts its effects through two GPCR-receptor subtypes, ETA and ETB; the former predominates in the rat myocardium ADDIN REFMGR.CITE Hilal-Dandan1997665Endothelin ETA receptor regulates signaling and ANF gene expression via multiple G protein-linked pathwaysJournal665Endothelin ETA receptor regulates signaling and ANF gene expression via multiple G protein-linked pathwaysHilal-Dandan,R.Ramirez,M.T.Villegas,S.Gonzalez,A.Endo-Mochizuki,Y.Brown,J.H.Brunton,L.L.1997/1analysisAnimalsAtrial Natriuretic FactorCa(2+)-Calmodulin Dependent Protein KinaseCyclic AMPEndothelinsGene ExpressionGenesgeneticsGTP-Binding ProteinsHydrolysisLigandsLuciferasesmetabolismpharmacologyPhosphatidylinositolsphysiologyPolymerase Chain ReactionPromoter Regions (Genetics)RatsRats,Sprague-DawleyReceptors,EndothelinReverse Transcriptase Polymerase Chain ReactionRNA,MessengerSignal TransductionNot in FileH130H137Am.J Physiol.2721 Pt 2Am.J Physiol.1134. Heart failure in rats leads to an increased ETA receptor density ADDIN REFMGR.CITE Sakai1996668Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heartJournal668Endogenous endothelin-1 participates in the maintenance of cardiac function in rats with congestive heart failure. Marked increase in endothelin-1 production in the failing heartSakai,S.Miyauchi,T.Sakurai,T.Kasuya,Y.Ihara,M.Yamaguchi,I.Goto,K.Sugishita,Y.1996/3/15analysisAnimalsbloodBlood Pressureclinicalcontractilityendothelin-1Endothelinsetiologygeneticsheartheart failureHeart Failure,Congestiveheart rateHemodynamic ProcessesMalemethodsmodelPeptides,CyclicpharmacologyphysiologyphysiopathologyPressureProtein PrecursorsRatsRats,Sprague-DawleyReninRNA,MessengerSignal TransductionsurgeryNot in File12141222Circulation.936Circulation.1133 . U p o n a c t i v a t i o n o f t h e r e c e p t o r , P L C - i s a c t i v a t e d ( w i t h d o w n s t r e a m a c t i v a t i o n o f t h e c a l c i n e u r i n / N F A T p a t h w a y ) , I P 3 a n d D A G a r e r e l e a s e d f r o m t h e c e l l m e m b r a n e ( w i t h s u b s e q u e n t a c t i v a t i o n o f P K C ) a n d t h e s m a l l G T P b i n d i n g p r o t e i n s R h o A a n d R a s a r e a c t i vated ADDIN REFMGR.CITE Sugden2003663An overview of endothelin signaling in the cardiac myocyteJournal663An overview of endothelin signaling in the cardiac myocyteSugden,P.H.2003/8Animalsapoptosiscalciumdrug effectsEndothelinsEnzyme ActivationHumansHydrolysismetabolismMitogen-Activated Protein KinasesModels,BiologicalMyocytes,CardiacpharmacologyProtein IsoformsProtein Kinase CProtein KinasesSignal TransductionSodiumTranscription FactorsTranscription,GeneticNot in File871886J Mol.Cell Cardiol.358J Mol.Cell Cardiol.1Clerk2001666Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1Journal666Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1Clerk,A.Pham,F.H.Fuller,S.J.Sahai,E.Aktories,K.Marais,R.Marshall,C.Sugden,P.H.2001/2AnimalsAtrial Natriuretic FactorCardiomegalyCells,Culturedcytologydrug effectsendothelin-1Enzyme ActivationetiologyGene Expression RegulationgeneticsGuanosine TriphosphateHumanshypertrophyMAP Kinase Kinase Kinase 1metabolismMitogen-Activated Protein KinasesMyocardiumNOpathologypharmacologyPhenylephrinePhosphorylationProtein KinasesProtein-Serine-Threonine KinasesProteinsProto-Oncogene Proteins c-rafrac1 GTP-Binding ProteinRatsRhorhoA GTP-Binding ProteinTransfectionNot in File11731184Mol.Cell Biol.214Mol.Cell Biol.1129;135. Mediated by calcineurin-NFAT signaling, ET-1 transactivates the pro-survival transcription factor bcl-2 in cardiomyocytes, protecting the heart from apoptosis ADDIN REFMGR.CITE Kawamura2004746Endothelin-1-Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac MyocytesJournal746Endothelin-1-Dependent Nuclear Factor of Activated T Lymphocyte Signaling Associates With Transcriptional Coactivator p300 in the Activation of the B Cell Leukemia-2 Promoter in Cardiac MyocytesKawamura,TeruhisaOno,KohMorimoto,TatsuyaAkao,MasaharuIwai-Kanai,EriWada,HiromichiSowa,NaoyaKita,ToruHasegawa,Koji2004/6/11apoptosisCalcineurinendothelin-1heartNFATRatssurvivalheart failureNot in File14921499Circ Res9411http://circres.ahajournals.org/cgi/content/abstract/94/11/1492Circ Res1136. In addition, ETA receptor activation (as AT1R and MR activation) is associated with activation of P I 3 K s u b t y p e p 1 1 0 a n d t r a n s a c t i v a t i o n o f t h e E G F r e c e p t o r . T h i s t r a n s a c t i v a t i o n i s m e d i a t e d b y a d i s i n t e g r i n a n d m e t a l l o p r o t e a s e 1 2 ( A D A M - 1 2 ) A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > A s a k u r a < / A u t h o r > < Y e a r > 2 0 0 2 < / Y e a r > < R e c N u m > 6 6 7 < / R e c N u m > < I D T e x t > C a r d i a c h y pertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyJournal667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyAsakura,M.Kitakaze,M.Takashima,S.Liao,Y.Ishikura,F.Yoshinaka,T.Ohmoto,H.Node,K.Yoshino,K.Ishiguro,H.Asanuma,H.Sanada,S.Matsumura,Y.Takeda,H.Beppu,S.Tada,M.Hori,M.Higashiyama,S.2002/1ADAM Proteinsanalogs & derivativesAngiotensin IIAnimalsantagonists & inhibitorsAorta,ThoracicCardiomegalyDisease Models,AnimalDisintegrinsdrug effectsdrug therapyEpidermal Growth FactorgeneticsGlycineGPCRGTP-Binding ProteinsheartHeart VentriclesHydroxamic AcidsHypertensionhypertrophyMaleMembrane ProteinsmetabolismMetalloendopeptidasesMicepharmacologyPhenylephrineProtease InhibitorsProtein Processing,Post-TranslationalRatsReceptor,Epidermal Growth FactorSignal TransductionsurgerySystoletherapeutic usetherapyTrans-Activation (Genetics)Not in File3540Nat.Med.81Nat.Med.136. Blocking ADAM-12 signaling prevents the development of hypertrophy in mice subjected to TAC, improving systolic function at the same time ADDIN REFMGR.CITE Asakura2002667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyJournal667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyAsakura,M.Kitakaze,M.Takashima,S.Liao,Y.Ishikura,F.Yoshinaka,T.Ohmoto,H.Node,K.Yoshino,K.Ishiguro,H.Asanuma,H.Sanada,S.Matsumura,Y.Takeda,H.Beppu,S.Tada,M.Hori,M.Higashiyama,S.2002/1ADAM Proteinsanalogs & derivativesAngiotensin IIAnimalsantagonists & inhibitorsAorta,ThoracicCardiomegalyDisease Models,AnimalDisintegrinsdrug effectsdrug therapyEpidermal Growth FactorgeneticsGlycineGPCRGTP-Binding ProteinsheartHeart VentriclesHydroxamic AcidsHypertensionhypertrophyMaleMembrane ProteinsmetabolismMetalloendopeptidasesMicepharmacologyPhenylephrineProtease InhibitorsProtein Processing,Post-TranslationalRatsReceptor,Epidermal Growth FactorSignal TransductionsurgerySystoletherapeutic usetherapyTrans-Activation (Genetics)Not in File3540Nat.Med.81Nat.Med.136. Finally, ET-1 signaling leads to activation of the MAPK cascade involving ERK1/2 ADDIN REFMGR.CITE Sugden2003663An overview of endothelin signaling in the cardiac myocyteJournal663An overview of endothelin signaling in the cardiac myocyteSugden,P.H.2003/8Animalsapoptosiscalciumdrug effectsEndothelinsEnzyme ActivationHumansHydrolysismetabolismMitogen-Activated Protein KinasesModels,BiologicalMyocytes,CardiacpharmacologyProtein IsoformsProtein Kinase CProtein KinasesSignal TransductionSodiumTranscription FactorsTranscription,GeneticNot in File871886J Mol.Cell Cardiol.358J Mol.Cell Cardiol.1129. In summary, ET-1 is associated with a myriad of signaling pathways, but the relative importance and interdependence of these pathways in ET-1s pro-hypertrophic action are not yet fully clear. In patients with PAH associated heart failure, the direct effects of ET-1 signaling on the heart are mixed with its stimulation of pulmonary vasoconstriction and vascular remodeling.
Prostaglandins
For more than a decade, prostaglandins (PGs) have been the cornerstone of PAH treatment ADDIN REFMGR.CITE Paramothayan2005564Prostacyclin for pulmonary hypertension in adultsJournal564Prostacyclin for pulmonary hypertension in adultsParamothayan,N.S.Lasserson,T.J.Wells,A.U.Walters,E.H.2005/4/18Adultanalogs & derivativesanalysisAntihypertensive Agentsdrug therapyepoprostenolexerciseHumansHypertensionHypertension,PulmonaryNOPlatelet Aggregationprostacyclinpulmonary hypertensionRandomized Controlled Trialstherapeutic usetherapytreprostinilNot in FileCD002994Cochrane.Database.Syst.Rev.2Cochrane.Database.Syst.Rev.1137. However, little is still known about their mode of action in the heart. The effects of PGI2 and 4 related, naturally occurring, cyclooxygenase metabolit e s ( p r o s t a n o i d s ) P G D 2 , P G E 1 , P G E 2 , a n d P G F 2 a r e c e l l t y p e s p e c i f i c a n d d e p e n d o n t h e a c t i v a t i o n o f a s p e c i f i c P G r e c e p t o r s u b t y p e ( G P C R s c o u p l e d t o i n h i b i t i n g o r s t i m u l a t i n g G p r o t e i n s ) A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > P i e r c e < / A u t h o r > < Y e a r > 1 9 9 8 < / Year>558Prostanoid receptor heterogeneity through alternative mRNA splicingJournal558Prostanoid receptor heterogeneity through alternative mRNA splicingPierce,K.L.Regan,J.W.1998Alternative SplicingAnimalsbiosynthesisgeneticsHumansIsomerismmetabolismpharmacologyprostacyclinRatsReceptors,ProstaglandinRNA,MessengerNot in File14791483Life Sci.6217-18Life Sci.1138. Through either inhibition or stimulation of AC, PGs affect platelet aggregation, vascular tone and growth and proliferation of endothelial cells, smooth muscle cells and fibroblasts. It is generally assumed that the therapeutic effect of PGs in PAH comes about by induction of pulmonary vasodilatation and inhibition of vascular remodeling ADDIN REFMGR.CITE Olschewski2004559Prostacyclin and its analogues in the treatment of pulmonary hypertensionJournal559Prostacyclin and its analogues in the treatment of pulmonary hypertensionOlschewski,H.Rose,F.Schermuly,R.Ghofrani,H.A.Enke,B.Olschewski,A.Seeger,W.2004/5adverse effectsanalogs & derivativesdrug therapyepidemiologyepoprostenolHumansHypertensionHypertension,PulmonaryiloprostmetabolismModels,BiologicalMolecular StructurepharmacokineticspharmacologyPhosphodiesterase InhibitorsphysiopathologyprostacyclinProstaglandinsPulmonary Arterypulmonary hypertensiontherapeutic usetherapytreprostinilNot in File139153Pharmacol.Ther.1022Pharmacol.Ther.1139. It has to be recognized, however, that PGs have important direct effects on the heart. In patients with severe heart failure, i.v. administration of epoprostenol (synthetic PGI2) results in an immediate and substantial increase in cardiac output and a reduction in cardiac filling pressures ADDIN REFMGR.CITE Yui1982560Prostacyclin therapy in patients with congestive heart failureJournal560Prostacyclin therapy in patients with congestive heart failureYui,Y.Nakajima,H.Kawai,C.Murakami,T.1982/8AgedAldosteronebloodCapillariescardiac outputdrug effectsdrug therapyEpinephrineepoprostenolFemaleheartheart failureHeart Failure,Congestiveheart rateHumansMaleMiddle AgedNorepinephrinePlatelet AggregationprostacyclinProstaglandinsPulmonary Capillary Wedge PressurePulmonary Wedge PressureRenintherapeutic usetherapyVascular ResistanceNot in File320324Am.J.Cardiol.502Am.J.Cardiol.1140. Whereas this could follow reflex tachycardia and pulmonary vasodilation with improved right ventriculoarterial coupling ADDIN REFMGR.CITE Yui1982560Prostacyclin therapy in patients with congestive heart failureJournal560Prostacyclin therapy in patients with congestive heart failureYui,Y.Nakajima,H.Kawai,C.Murakami,T.1982/8AgedAldosteronebloodCapillariescardiac outputdrug effectsdrug therapyEpinephrineepoprostenolFemaleheartheart failureHeart Failure,Congestiveheart rateHumansMaleMiddle AgedNorepinephrinePlatelet AggregationprostacyclinProstaglandinsPulmonary Capillary Wedge PressurePulmonary Wedge PressureRenintherapeutic usetherapyVascular ResistanceNot in File320324Am.J.Cardiol.502Am.J.Cardiol.1Kerbaul2007561How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertensionJournal561How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertensionKerbaul,F.Brimioulle,S.Rondelet,B.Dewachter,C.Hubloue,I.Naeije,R.2007/4/15cardiac outputcontractilityDogsepoprostenolheartheart failureHypertensionmethodsmodelphysiologyprostacyclinpulmonary hypertensionright ventricletherapyVascular ResistanceNot in File846850Am.J.Respir.Crit Care Med.1758Am.J.Respir.Crit Care Med.121;140, molecular effects on cardiac cells and signaling pathways are also possible. In a model of flow-associated PAH, the synthetic PGI2 analog iloprost improved RV contractility and capillary-to-myocyte ratio (but not density), independently from a change in RV afterload ADDIN REFMGR.CITE van Albada2006649Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertensionJournal649Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertensionvan Albada,M.E.Berger,R.M.Niggebrugge,M.van,Veghel R.Cromme-Dijkhuis,A.H.Schoemaker,R.G.2006/11/7AnimalsArachidonic AcidAspirinBlood Pressureblood supplyCapillariesCardiologycongenitalcontractilityDisease Models,Animaldrug effectsdrug therapyechocardiographyGene ExpressiongeneticsheartHeart VentriclesHypertensionHypertension,PulmonaryhypertrophyiloprostLungMalemetabolismmodelmonocrotalinemortalityMyocardiumOrgan SizepathologyphysiopathologyPlatelet Aggregation InhibitorsPressureprostacyclinPulmonary ArteryPulmonary Circulationpulmonary hypertensionRatsRats,WistarReceptors,Vascular Endothelial Growth FactorremodelingshuntSurvival Ratetherapeutic usetherapyVascular Endothelial Growth Factor AVentricular RemodelingNot in File107116Eur.J Pharmacol.5491-3Eur.J Pharmacol.115. PGI2 has been reported to suppress pressure overloadinduced cardiac hypertrophy via the inhibition of both cardiomyocyte hypertrophy and cardiac fibrosis. Both effects are considered to originate from the action on non-cardiomyocytes, but the underlying mechanisms are undetermined ADDIN REFMGR.CITE Hara2005563Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptorJournal563Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptorHara,A.Yuhki,K.Fujino,T.Yamada,T.Takayama,K.Kuriyama,S.Takahata,O.Karibe,H.Okada,Y.Xiao,C.Y.Ma,H.Narumiya,S.Ushikubi,F.2005/7/5analogs & derivativesanalysisAnimalsAortaBiological MarkersbloodCardiomegalyCell EnlargementcomplicationsCyclic AMPdeficiencyDisease Models,AnimalepoprostenoletiologyFemalefibrosisgeneticsheartHypertensionhypertrophymethodsMiceMice,KnockoutmodelMyocytes,CardiacNOpathologypharmacologyphysiologyReceptors,EpoprostenolRNA,MessengerNot in File8492Circulation.1121Circulation.140.
Atrial and brain natriuretic peptides (ANP and BNP)
The expression of natriuretic peptides is increased both in PAH a n d i n h e a r t f a i l u r e ; t h e p r i m a r y s t i m u l u s i s i n c r e a s e d v e n t r i c u l a r s t r e t c h , b u t t h i s r e s p o n s e i s m o d u l a t e d b y m a n y o t h e r f a c t o r s , s u c h a s A T I I , E T - 1 , c i r c u l a t i n g c a t e c h o l a m i n e s , 1 a n d 2 s t i m u l a t i o n a n d h y p o x i a A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r >Yap2004471The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertensionJournal471The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertensionYap,L.B.Ashrafian,H.Mukerjee,D.Coghlan,J.G.Timms,P.M.2004/10AnimalsbloodCardiologyclinicaldiagnosisheartHumansHypertensionHypertension,PulmonaryhypertrophymortalityNatriuretic PeptidesPAHphysiologyphysiopathologypulmonary hypertensiontherapyVascular ResistanceVentricular Dysfunction,RightNot in File847856Clin.Biochem.3710Clin.Biochem.1141. Integrins are important for linking stress to increased atrial natriuretic peptide (ANP) gene expression ADDIN REFMGR.CITE Ross1998398Beta1 integrins participate in the hypertrophic response of rat ventricular myocytesJournal398Beta1 integrins participate in the hypertrophic response of rat ventricular myocytesRoss,R.S.Pham,C.Shai,S.Y.Goldhaber,J.I.Fenczik,C.Glembotski,C.C.Ginsberg,M.H.Loftus,J.C.1998/6/15Adrenergic alpha-AgonistsAtrial Natriuretic FactorhypertrophyIntegrinsheart failureNot in File11601172Circ.Res.8211Circ.Res.1142. ANP and brain natriuretic peptide (BNP) bind to the natriuretic peptide receptors NPR-A, NPR-B and NPR-C. Upon binding of the natriuretic peptides to NPR-A, the particulate guanylate cyclase (pGC) that is linked to the receptor produces cyclic guanosine monophosphate (cGMP), which in turn activates protein kinase G (PKG, see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e3.ppt"fig. e3 and below) ADDIN REFMGR.CITE McFarlane2003420Role of the natriuretic peptide system in cardiorenal protectionJournal420Role of the natriuretic peptide system in cardiorenal protectionMcFarlane,S.I.Winer,N.Sowers,J.R.2003/12/8AnimalsCardiovascular Diseasesdrug therapyHumansHypertensionKidney DiseasesNatriuretic PeptidesphysiologyphysiopathologyProtease Inhibitorsreviewtherapeutic useNot in File26962704Arch.Intern.Med.16322Arch.Intern.Med.1143. Natriuretic peptides are primarily involved in vasodilation and fluid balance. By inhibiting RAS and the sympathetic system ADDIN REFMGR.CITE Yap2004471The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertensionJournal471The natriuretic peptides and their role in disorders of right heart dysfunction and pulmonary hypertensionYap,L.B.Ashrafian,H.Mukerjee,D.Coghlan,J.G.Timms,P.M.2004/10AnimalsbloodCardiologyclinicaldiagnosisheartHumansHypertensionHypertension,PulmonaryhypertrophymortalityNatriuretic PeptidesPAHphysiologyphysiopathologypulmonary hypertensiontherapyVascular ResistanceVentricular Dysfunction,RightNot in File847856Clin.Biochem.3710Clin.Biochem.1141, they indirectly suppress cardiac hypertrophy and fetal gene expression. Moreover, there is evidence that ANP/BNP induced cGMP signaling directly attenuates cardiomyocyte hypertrophy in response to TAC ADDIN REFMGR.CITE Zahabi2003675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsJournal675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsZahabi,A.Picard,S.Fortin,N.Reudelhuber,T.L.Deschepper,C.F.2003/11/28Adenylate CyclaseAnimalsAortabiosynthesisBlood PressureBlotting,NorthernchemistryConstrictionCos CellsCyclic GMPDNA,Complementarydrug effectsechocardiographyenzymologyGene ExpressiongeneticsGuanylate CyclaseheartHypertensionhypertrophyIsoproterenolMalemetabolismMiceMice,Inbred C3HMice,Inbred C57BLMice,KnockoutMice,TransgenicmodelMyocardiumNOpathologyPeptidespharmacologyProtein Structure,TertiaryRatsReceptors,Atrial Natriuretic FactorremodelingResearchRNA,MessengerTissue DistributionTransfectionTransgenesNot in File4769447699J Biol.Chem.27848J Biol.Chem.139, inhibits cardiomyocyte apoptosis via nuclear accumulation of zyxin and Akt1 ADDIN REFMGR.CITE Kato2005481Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and AktJournal481Atrial natriuretic peptide promotes cardiomyocyte survival by cGMP-dependent nuclear accumulation of zyxin and AktKato,T.Muraski,J.Chen,Y.Tsujita,Y.Wall,J.Glembotski,C.C.Schaefer,E.Beckerle,M.Sussman,M.A.2005/10Active Transport,Cell NucleusAnimalsAnimals,NewbornapoptosisAtrial Natriuretic FactorCell DeathCell NucleusCell SurvivalCells,CulturedCyclic GMPcytologyCytoskeletal Proteinsdrug effectsgeneticsheartHumansmetabolismMiceMice,KnockoutMyocytes,CardiacpharmacologyProto-Oncogene Proteins c-aktRatsRats,Sprague-DawleySignal TransductionsurvivalNot in File27162730J.Clin.Invest.11510Journal of Clinical InvestigationJ.Clin.Invest.1144 and prevents myocardial fibrosis through inhibition of cardiac fibroblasts ADDIN REFMGR.CITE Redondo1998475Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblastsJournal475Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblastsRedondo,J.Bishop,J.E.Wilkins,M.R.1998/83',5'-Cyclic-GMP PhosphodiesteraseAdultAngiotensin IIAnimalsantagonists & inhibitorsAtrial Natriuretic FactorbiosynthesisCattleCells,CulturedCollagenCyclic GMPcytologyDnaExtracellular MatrixExtracellular Matrix ProteinsfibroblastFibroblastsHumansHypertensionMalemetabolismMitogensMyocardial InfarctionMyocardiumNOpharmacologyPhosphodiesterase InhibitorsRatsRats,Inbred WKYReceptors,Atrial Natriuretic FactorTransforming Growth Factor beta1Not in File14551462Br.J.Pharmacol.1247Br.J.Pharmacol.1Tamura2000474Cardiac fibrosis in mice lacking brain natriuretic peptideJournal474Cardiac fibrosis in mice lacking brain natriuretic peptideTamura,N.Ogawa,Y.Chusho,H.Nakamura,K.Nakao,K.Suda,M.Kasahara,M.Hashimoto,R.Katsuura,G.Mukoyama,M.Itoh,H.Saito,Y.Tanaka,I.Otani,H.Katsuki,M.2000/4/11AnimalsBase SequencebiosynthesisBlood Pressurebrain natriuretic peptideclinicalExtracellular MatrixfibroblastFibroblastsfibrosisgeneticsheartheart failureHypertensionhypertrophyMiceMice,KnockoutMicroscopy,ElectronMyocardial InfarctionMyocardiumNatriuretic Peptide,BrainNOOligonucleotides,AntisensepathologyPhenotypephysiologyremodelingRNA,MessengerultrastructureVentricular PressureVentricular RemodelingWater-Electrolyte BalanceNot in File42394244Proc.Natl.Acad.Sci.U.S.A.978Proc.Natl.Acad.Sci.U.S.A.133;145. Binding of ANP and BNP to NPR-C is followed by endocytosis and lysomal degradation ADDIN REFMGR.CITE Almeida1989472Clearance function of type C receptors of atrial natriuretic factor in ratsJournal472Clearance function of type C receptors of atrial natriuretic factor in ratsAlmeida,F.A.Suzuki,M.Scarborough,R.M.Lewicki,J.A.Maack,T.1989/2AnimalsAtrial Natriuretic FactorChromatography,High Pressure LiquidHomeostasisHydrolysisIodine RadioisotopesMaleMetabolic Clearance RatemetabolismpharmacokineticsphysiologyRatsRats,Inbred StrainsReceptors,Atrial Natriuretic FactorReceptors,Cell SurfaceStructure-Activity RelationshipNot in FileR469R475Am.J.Physiol.2562 Pt 2Am.J.Physiol.1146, but more important for peptide clearance is inactivation by neutral endopeptidase (NEP) ADDIN REFMGR.CITE Soleilhac1992473A 94-kDa protein, identified as neutral endopeptidase-24.11, can inactivate atrial natriuretic peptide in the vascular endotheliumJournal473A 94-kDa protein, identified as neutral endopeptidase-24.11, can inactivate atrial natriuretic peptide in the vascular endotheliumSoleilhac,J.M.Lucas,E.Beaumont,A.Turcaud,S.Michel,J.B.Ficheux,D.Fournie-Zaluski,M.C.Roques,B.P.1992/4Amino Acid SequenceAnimalsantagonists & inhibitorsAtrial Natriuretic FactorAutoradiographyChromatography,High Pressure LiquidDithiothreitoldrug effectsElectrophoresisElectrophoresis,Polyacrylamide GelendotheliumEndothelium,VascularEnkephalin,Leucine-2-AlanineHumansHydrolysismetabolismMolecular Sequence DataNeprilysinpharmacologyRatsSodiumSulfhydryl CompoundsThiorphanNot in File609614Mol.Pharmacol.414Mol.Pharmacol.1147.
Nitric oxide, cyclic guanosine monophosphate and protein kinase G
cGMP is a ubiquitous intracellular secondary messenger in the cardiovascular system. Whereas the natriuretic peptides activate pGC, NO induces the formation of cGMP through activation of soluble guanylate cyclase (sGC, see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e3.ppt"fig. e3) ADDIN REFMGR.CITE McFarlane2003420Role of the natriuretic peptide system in cardiorenal protectionJournal420Role of the natriuretic peptide system in cardiorenal protectionMcFarlane,S.I.Winer,N.Sowers,J.R.2003/12/8AnimalsCardiovascular Diseasesdrug therapyHumansHypertensionKidney DiseasesNatriuretic PeptidesphysiologyphysiopathologyProtease Inhibitorsreviewtherapeutic useNot in File26962704Arch.Intern.Med.16322Arch.Intern.Med.1143. cGMP is degraded by the action of PDEs; some PDE subtypes hydrolyze cGMP only (PDE5, PDE6, PDE9), whereas others degrade cAMP (PDE3, PDE4, PDE7, PDE8) or both cGMP and cAMP (PDE1, PDE2). ADDIN REFMGR.CITE Moreland1999674Sildenafil Citrate, a Selective Phosphodiesterase Type 5 Inhibitor:Journal674Sildenafil Citrate, a Selective Phosphodiesterase Type 5 Inhibitor:Moreland,R.B.Goldstein,I.,IKim,N.N.Traish,A.1999/4clinicalcontractilityendotheliumHydrolysismetabolismmuscleMuscle CellsMuscle Relaxationnitric oxideNOpharmacologyphysiologyreviewsildenafilNot in File97104Trends Endocrinol.Metab.103Trends Endocrinol.Metab.1148 Whereas a role for cGMP in cardiac contractility, lusitropy and ion channel responsivity is well established, the extent to which natriuretic peptides versus NO mediate these effects is less clear ADDIN REFMGR.CITE Hare2005438NO/redox disequilibrium in the failing heart and cardiovascular systemJournal438NO/redox disequilibrium in the failing heart and cardiovascular systemHare,J.M.Stamler,J.S.2005/3adverse effectsAnimalsbloodCardiac Output,LowCardiologyCardiovascular AgentsCardiovascular Systemcytologydrug therapyheartHomeostasisHumansmetabolismMyocardiumnitric oxideOxidation-ReductionOxygenpathologyPhenotypephysiologyphysiopathologyReactive Nitrogen Speciesreactive oxygen speciesSignal Transductiontherapeutic useNot in File509517J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1149. Part of the divergent actions of natriuretic peptides and NO seem to result from the fact that they are involved in the generation of cGMP in different subcelllular locations: at the plasma membrane in case of the former and in the cytosol in case of the latter. This compartimentalization is enhanced by the fact that PDE5 controls the soluble but not the particulate cGMP pool ADDIN REFMGR.CITE Castro2006673Cyclic guanosine monophosphate compartmentation in rat cardiac myocytesJournal673Cyclic guanosine monophosphate compartmentation in rat cardiac myocytesCastro,L.R.Verde,I.Cooper,D.M.Fischmeister,R.2006/5/91-Methyl-3-isobutylxanthine3',5'-Cyclic-GMP PhosphodiesteraseAdenineAdultanalogs & derivativesanalysisAnimalsantagonists & inhibitorsAtrial Natriuretic FactorBiological Transportbrain natriuretic peptideCell CompartmentationCell MembranechemistryCyclic AMPCyclic GMPcytologydrug effectsHeart VentriclesHumansIon Channel GatingIon ChannelsIsoenzymesMalemetabolismmethodsmuscleMyocytes,CardiacNatriuretic Peptide,BrainNatriuretic Peptidesnitric oxideNitric Oxide DonorsNOPeptidespharmacologyPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesphysiologyPiperazinesRatsRats,WistarRecombinant Fusion ProteinsSarcolemmaSecond Messenger SystemssildenafilSolubilityultrastructureNot in File22212228Circulation.11318Circulation.1150.
The effect of cGMP on myocardial contractility depends on its interaction with the PDEs and cAMP. Theoretically, cGMP can decrease contractility by decreasing cAMP concentrations through inhibition of AC and induction of PDE2 (see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e3.ppt"fig. e3) ADDIN REFMGR.CITE Semigran2005671Type 5 phosphodiesterase inhibition: the focus shifts to the heartJournal671Type 5 phosphodiesterase inhibition: the focus shifts to the heartSemigran,M.J.2005/10/253',5'-Cyclic-GMP PhosphodiesteraseDiastoledrug effectsheartHumansmetabolismMyocardial ContractionpharmacologyPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesphysiologyPiperazinesReceptors,Adrenergic,betaNot in File25892591Circulation.11217Circulation.1Zaccolo2007682cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiologyJournal682cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiologyZaccolo,M.Movsesian,M.A.2007/6/8heartHydrolysisProteinsResearchNot in File15691578Circ.Res.10011Circ.Res.1151;152. In addition, phosphorylation of troponin I by a cGMP-dependent protein kinase can decrease the sensitivity of the contractile apparatus to Ca2+ and accelerate myocardial relaxation ADDIN REFMGR.CITE Semigran2005671Type 5 phosphodiesterase inhibition: the focus shifts to the heartJournal671Type 5 phosphodiesterase inhibition: the focus shifts to the heartSemigran,M.J.2005/10/253',5'-Cyclic-GMP PhosphodiesteraseDiastoledrug effectsheartHumansmetabolismMyocardial ContractionpharmacologyPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesphysiologyPiperazinesReceptors,Adrenergic,betaNot in File25892591Circulation.11217Circulation.1151. On the other hand, it was recently shown in PAH patients and MCT induced RV hypertrophy that cGMP can in fact increase contractility by increasing cAMP concentrations ADDIN REFMGR.CITE Nagendran2007741Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves ContractilityJournal741Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves ContractilityNagendran,JayanArcher,Stephen L.Soliman,DanielGurtu,VikramMoudgil,RohitHaromy,AloisAubin,ChantalWebster,LindaRebeyka,Ivan M.Ross,David B.Light,Peter E.Dyck,Jason R.B.Michelakis,Evangelos D.2007/7/2contractilityheartHypertensionMyocardiumright ventriclesildenafilNot in File238248Circulation1163http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.106.655266v1Circulation1153. The authors explained this apparent paradox by cGMP related inhibition of the cGMP sensitive PDE3. They also showed that compared to the normal RV, RV hypertrophy (both human and experimentally induced) is associated with a considerable decrease in PKG activity. At the same time, PDE5 was only expressed in the hypertrophic RV and not in the normal RV ADDIN REFMGR.CITE Nagendran2007741Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves ContractilityJournal741Phosphodiesterase Type 5 Is Highly Expressed in the Hypertrophied Human Right Ventricle, and Acute Inhibition of Phosphodiesterase Type 5 Improves ContractilityNagendran,JayanArcher,Stephen L.Soliman,DanielGurtu,VikramMoudgil,RohitHaromy,AloisAubin,ChantalWebster,LindaRebeyka,Ivan M.Ross,David B.Light,Peter E.Dyck,Jason R.B.Michelakis,Evangelos D.2007/7/2contractilityheartHypertensionMyocardiumright ventriclesildenafilNot in File238248Circulation1163http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.106.655266v1Circulation1153.
cGMP/PKG signaling protects the heart from apoptosis ADDIN REFMGR.CITE Das2005681Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signalingJournal681Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signalingDas,A.Xi,L.Kukreja,R.C.2005/4/13',5'-Cyclic-GMP PhosphodiesteraseAdultAnimalsapoptosisbcl-X ProteinBenzimidazolesBlotting,WesternCarbocyaninesCardiologyCaspase 3CaspasesCell DeathCell SurvivalCells,CulturedchemistryDNA PrimersDNA,Complementarydrug effectseNOSEnzyme ActivationEnzyme InhibitorsImmunohistochemistryIn Situ Nick-End LabelingischemiaL-Lactate DehydrogenaselactateMaleMembrane PotentialsmetabolismMiceMice,Inbred C57BLMice,Inbred ICRMice,KnockoutmitochondriaMuscle CellsMyocytes,CardiacNecrosisNG-Nitroarginine Methyl Esternitric oxideNitric Oxide SynthaseNitric Oxide Synthase Type IINitric Oxide Synthase Type IIINOOxygenpathologypharmacologyPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesPiperazinesProto-Oncogene Proteins c-bcl-2Reverse Transcriptase Polymerase Chain ReactionSignal TransductionsildenafilTime FactorsTranscription,GeneticTrypan BlueUp-RegulationNot in File1294412955J Biol.Chem.28013J Biol.Chem.1Fisher2005678Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicityJournal678Phosphodiesterase-5 inhibition with sildenafil attenuates cardiomyocyte apoptosis and left ventricular dysfunction in a chronic model of doxorubicin cardiotoxicityFisher,P.W.Salloum,F.Das,A.Hyder,H.Kukreja,R.C.2005/4/53',5'-Cyclic-GMP PhosphodiesteraseAdultadverse effectsAnimalsapoptosisCardiologyCardiomyopathiesCaspase 3chemically inducedChronic DiseaseDoxorubicindrug effectsdrug therapyDrug Therapy,CombinationHeart Failure,CongestiveLigationMalemethodsMiceMice,Inbred ICRmodelMyocytes,CardiacpathologypharmacologyPhosphodiesterase InhibitorsPhosphoric Diester HydrolasesPiperazinesPremedicationPressureprevention & controlsildenafiltherapeutic useVentricular Dysfunction,LeftVentricular FunctionNot in File16011610Circulation.11113Circulation.1154;155 and blunts the hypertrophic response to pressure overload and isoproterenol, which is associated with inhibition of the calcineurin/NFAT pathway, PI3K/Akt1 signaling and ERK1/2 cascades ADDIN REFMGR.CITE Zahabi2003675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsJournal675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsZahabi,A.Picard,S.Fortin,N.Reudelhuber,T.L.Deschepper,C.F.2003/11/28Adenylate CyclaseAnimalsAortabiosynthesisBlood PressureBlotting,NorthernchemistryConstrictionCos CellsCyclic GMPDNA,Complementarydrug effectsechocardiographyenzymologyGene ExpressiongeneticsGuanylate CyclaseheartHypertensionhypertrophyIsoproterenolMalemetabolismMiceMice,Inbred C3HMice,Inbred C57BLMice,KnockoutMice,TransgenicmodelMyocardiumNOpathologyPeptidespharmacologyProtein Structure,TertiaryRatsReceptors,Atrial Natriuretic FactorremodelingResearchRNA,MessengerTissue DistributionTransfectionTransgenesNot in File4769447699J Biol.Chem.27848J Biol.Chem.1Fiedler2002676Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytesJournal676Inhibition of calcineurin-NFAT hypertrophy signaling by cGMP-dependent protein kinase type I in cardiac myocytesFiedler,B.Lohmann,S.M.Smolenski,A.Linnemuller,S.Pieske,B.Schroder,F.Molkentin,J.D.Drexler,H.Wollert,K.C.2002/8analogs & derivativesAnimalsAnimals,Newbornantagonists & inhibitorsbrain natriuretic peptideCalcineurinCalcium Channels,L-TypeCalcium SignalingCardiologyCardiomegalyCell EnlargementCells,CulturedCyclic GMPCyclic GMP-Dependent Protein KinasesDNA-Binding ProteinsEnzyme ActivationenzymologyGenesgeneticsheartHeart VentricleshypertrophyIon Channel GatingLuciferasesmetabolismmortalityMyocardiumNatriuretic Peptide,BrainNFATC Transcription Factorsnitric oxideNONuclear ProteinspharmacologyphysiologyphysiopathologyPlasmidsprevention & controlProbabilityPromoter Regions (Genetics)RatsRats,Sprague-DawleyRiskSignal TransductionThionucleotidesTranscription FactorsTranscription,GeneticTransfectionNot in File1136311368Proc.Natl.Acad.Sci.U.S.A.9917Proc.Natl.Acad.Sci.U.S.A.1Takimoto2005677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyJournal677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyTakimoto,E.Champion,H.C.Li,M.Belardi,D.Ren,S.Rodriguez,E.R.Bedja,D.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/21-Phosphatidylinositol 3-Kinase3',5'-Cyclic-GMP PhosphodiesteraseAnimalsAnimals,Newbornantagonists & inhibitorsBlood PressureCalcineurinCardiologyCardiomegalyConstrictionCyclic GMPCyclic GMP-Dependent Protein KinasesDNA-Binding Proteinsdrug effectsdrug therapyEnzyme ActivationenzymologyExtracellular Signal-Regulated MAP Kinasesgeneticsheartheart failureHemodynamic ProcesseshypertrophyMalemetabolismMiceMice,Inbred C57BLMice,TransgenicMyocardiumNFATC Transcription FactorsNuclear ProteinspathologypharmacologyPhosphodiesterase InhibitorsphysiologyPiperazinesPressureProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRatsRats,Sprague-Dawleyremodelingsildenafiltherapeutic useTranscription FactorsNot in File214222Nat.Med.112Nat.Med.139;42;156. PKG interacts in a complex way with RhoA signaling. Whereas PKG can phosphorylate RhoA, forcing its cytosolic location and thereby preventing downstream activation (a potentially additional way of counteracting pro-hypertrophic signals), a basal level of PKG is necessary for transcription and protein stabilization of this small GTP binding protein ADDIN REFMGR.CITE Sauzeau2003679RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activationJournal679RhoA expression is controlled by nitric oxide through cGMP-dependent protein kinase activationSauzeau,V.Rolli-Derkinderen,M.Marionneau,C.Loirand,G.Pacaud,P.2003/3/143T3 CellsAdultanalogs & derivativesanalysisAnimalsAortaArteriesBlotting,NorthernBlotting,WesternCells,CulturedchemistryCyclic GMPCyclic GMP-Dependent Protein KinasesCycloheximidecytologyEndothelium,VascularEnzyme ActivationenzymologyGene Expression RegulationHumansMalemetabolismMicemuscleMuscle CellsMutagenesis,Site-DirectedMyocytes,Smooth Musclenitric oxideNOpharmacologyPhosphorylationPlasmidsPromoter Regions (Genetics)Protein BindingProtein Synthesis InhibitorsPulmonary ArteryRatsRats,WistarReverse Transcriptase Polymerase Chain ReactionrhoA GTP-Binding ProteinRNA,MessengerSignal TransductionsildenafilSodiumThionucleotidesTime FactorsTranscription,GeneticTransfectionNot in File94729480J Biol.Chem.27811J Biol.Chem.1157.
It should be noted that NO plays many roles in the cardiovascular system, some of which are independent from its induction of sGC. Whereas some issues concerning nitrosative stress will be dealt with below, we refer to other reviews for a thorough discussion on how NO affects excitation-contraction coupling and myocardial relaxation, heart rate, myocardial energetics and myocardial substrate utilization, and on how NO can exert both beneficial and deleterious effects in pathological situations (ischemia-reperfusion, left ventricular hypertrophy, heart failure, transplant vasculopathy and rejection, myocarditis) ADDIN REFMGR.CITE Shah2000672Paracrine and autocrine effects of nitric oxide on myocardial functionJournal672Paracrine and autocrine effects of nitric oxide on myocardial functionShah,A.M.MacCarthy,P.A.2000/4Angiotensin IIAutocrine CommunicationCardiologyCardiovascular Diseasesdeficiencydiastolic functionEndothelial Cellsendothelin-1endotheliumEndothelium,Vascularheartheart failureheart rateHumanshypertrophymetabolismMyocarditisMyocardiumnitric oxideNitric Oxide SynthaseNOOxygenParacrine Communicationphysiologyphysiopathologyreactive oxygen speciesreviewSignal TransductionNot in File4986Pharmacol.Ther.861Pharmacol.Ther.1158.
Adrenomedullin
Adrenomedullin (AM) is another peptide that is upregulated in heart failure and could have important cardio-protective effects ADDIN REFMGR.CITE Nishikimi1995581Increased plasma levels of adrenomedullin in patients with heart failureJournal581Increased plasma levels of adrenomedullin in patients with heart failureNishikimi,T.Saito,Y.Kitamura,K.Ishimitsu,T.Eto,T.Kangawa,K.Matsuo,H.Omae,T.Matsuoka,H.1995/11/15AdenosineAdrenomedullinAdultAgedAged,80 and overAldosteroneAntihypertensive AgentsAtrial Natriuretic Factorbloodbrain natriuretic peptideCardiovascular SystemCase-Control StudiesCyclic AMPdrug therapyechocardiographyFemaleheartheart failureHeart Failure,CongestiveHumansHypertensionMalemethodsMiddle AgedNatriuretic Peptide,BrainNerve Tissue ProteinsNervous SystemNorepinephrinePeptidesphysiologyRadioimmunoassayReninRestsympathetic nervous systemTime FactorsVascular ResistanceNot in File14241431J.Am.Coll.Cardiol.266J.Am.Coll.Cardiol.1159. Circulating levels are also elevated in PAH and correlate strongly with right atrial pressure ADDIN REFMGR.CITE Kakishita1999582Increased plasma levels of adrenomedullin in patients with pulmonary hypertensionJournal582Increased plasma levels of adrenomedullin in patients with pulmonary hypertensionKakishita,M.Nishikimi,T.Okano,Y.Satoh,T.Kyotani,S.Nagaya,N.Fukushima,K.Nakanishi,N.Takishita,S.Miyata,A.Kangawa,K.Matsuo,H.Kunieda,T.1999/1administration & dosageAdministration,InhalationAdrenomedullinAgedAnalysis of VarianceAtrial Natriuretic FactorbloodBlood PressureCase-Control Studiesclinicaldrug therapyFemaleFollow-Up StudiesHeart CatheterizationHemodynamic ProcessesHumansHypertensionHypertension,PulmonaryLungMaleMiddle Agednitric oxidePeptidesphysiopathologyPulmonary Circulationpulmonary hypertensionRadioimmunoassayRegression Analysisstroke volumeVascular ResistanceVasodilator AgentsNot in File3339Clin.Sci.(Lond).961Clin.Sci.(Lond).1160. AM gene expression is promoted by various stimuli, including inflammation, hypoxia, oxidative stress, mechanical stress and activation of RAS and the sympathetic nervous system ADDIN REFMGR.CITE Ishimitsu2006583Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disordersJournal583Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disordersIshimitsu,T.Ono,H.Minami,J.Matsuoka,H.2006/9AdrenomedullinAmino Acid SequenceAnimalsbiosynthesisbloodBlood VesselsCarcinogensCardiovascular DiseasesCell Transplantationchemistryclinicaldrug therapyGene ExpressionGene Therapygeneticsheartheart failureHeart Failure,CongestiveHumansHypertensionHypertension,PulmonaryhypoxiainflammationInterleukin-6Kidney FailureMolecular Sequence DataMyocardial InfarctionMyocardiumNervous SystemOxidative StressphysiologyPolymorphism,Single NucleotidePromoter Regions (Genetics)Renin-Angiotensin SystemRiskSignal TransductionStresssympathetic nervous systemtherapeutic useTranscription FactorsNot in File909927Pharmacol.Ther.1113Pharmacol.Ther.1161. Its signaling compares to natriuretic peptides in many aspects: AM induces systemic and pulmonary vasodilatation and natriuresis, AM inhibits ET-1 signaling, AM inhibits RAS and the sympathetic nervous systems, AM inhibits fibroblast proliferation and AM is cleared by NEP. Surprisingly, binding of AM to its receptor results in activation of AC instead of pGC, which could be responsible for a possible positive inotropic effect of AM (although this is still controversial) ADDIN REFMGR.CITE Ishimitsu2006583Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disordersJournal583Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disordersIshimitsu,T.Ono,H.Minami,J.Matsuoka,H.2006/9AdrenomedullinAmino Acid SequenceAnimalsbiosynthesisbloodBlood VesselsCarcinogensCardiovascular DiseasesCell Transplantationchemistryclinicaldrug therapyGene ExpressionGene Therapygeneticsheartheart failureHeart Failure,CongestiveHumansHypertensionHypertension,PulmonaryhypoxiainflammationInterleukin-6Kidney FailureMolecular Sequence DataMyocardial InfarctionMyocardiumNervous SystemOxidative StressphysiologyPolymorphism,Single NucleotidePromoter Regions (Genetics)Renin-Angiotensin SystemRiskSignal TransductionStresssympathetic nervous systemtherapeutic useTranscription FactorsNot in File909927Pharmacol.Ther.1113Pharmacol.Ther.1161. As discussed above, chronic stimulation of AC may be detrimental for cardiac function. The fact that AM signaling mimics natriuretic peptide signaling could be due to its stimulating effect on endothelial NO synthase expression. Finally, AM stimulates Akt1 mediated angiogenesis (see below for details on the complex relation between Akt1 and angiogenesis) and inhibits endothelial and cardiomyocyte apoptosis ADDIN REFMGR.CITE Ishimitsu2006583Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disordersJournal583Pathophysiologic and therapeutic implications of adrenomedullin in cardiovascular disordersIshimitsu,T.Ono,H.Minami,J.Matsuoka,H.2006/9AdrenomedullinAmino Acid SequenceAnimalsbiosynthesisbloodBlood VesselsCarcinogensCardiovascular DiseasesCell Transplantationchemistryclinicaldrug therapyGene ExpressionGene Therapygeneticsheartheart failureHeart Failure,CongestiveHumansHypertensionHypertension,PulmonaryhypoxiainflammationInterleukin-6Kidney FailureMolecular Sequence DataMyocardial InfarctionMyocardiumNervous SystemOxidative StressphysiologyPolymorphism,Single NucleotidePromoter Regions (Genetics)Renin-Angiotensin SystemRiskSignal TransductionStresssympathetic nervous systemtherapeutic useTranscription FactorsNot in File909927Pharmacol.Ther.1113Pharmacol.Ther.1Kim2003586Angiogenic role of adrenomedullin through activation of Akt, mitogen-activated protein kinase, and focal adhesion kinase in endothelial cellsJournal586Angiogenic role of adrenomedullin through activation of Akt, mitogen-activated protein kinase, and focal adhesion kinase in endothelial cellsKim,W.Moon,S.O.Sung,M.J.Kim,S.H.Lee,S.So,J.N.Park,S.K.2003/10Adrenomedullinanatomy & histologyantagonists & inhibitorsbiosynthesisCell MovementCells,CulturedclinicalDnaEndothelial CellsEndothelium,VascularEnzyme ActivationenzymologyFocal Adhesion Kinase 1Focal Adhesion Protein-Tyrosine KinasesHumansmetabolismMitogen-Activated Protein KinasesModels,BiologicalNeovascularization,PhysiologicPeptidespharmacologyPhosphorylationphysiologyProtein-Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktResearchSignal TransductionTyrosineNot in File19371939FASEB J.1713The FASEB JournalFASEB J.1161;162.
Apelin
Apelin is a recently discovered n e u r o h o r m o n e t h a t i s u p r e g u l a t e d i n h e a r t f a i l u r e a n d i s c h e m i a ( v i a h y p o x i a i n d u c i b l e f a c t o r , H I F - 1 ) a n d s e e m s t o h a v e n a t r i u r e t i c , v a s o d i l a t i n g , a n t i - p r o l i f e r a t i v e a n d p o s i t i v e i n o t r o p i c e f f e c t s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > R o n k a i n e n < / A u t h o r>2007556Hypoxia inducible factor regulates the cardiac expression and secretion of apelinJournal556Hypoxia inducible factor regulates the cardiac expression and secretion of apelinRonkainen,V.P.Ronkainen,J.J.Hanninen,S.L.Leskinen,H.Ruas,J.L.Pereira,T.Poellinger,L.Vuolteenaho,O.Tavi,P.2007/3/6bloodBlood PressureGene ExpressionHIF-1alphahypoxiaischemiamodelMyocardial InfarctionMyocardiumOxygenPeptidespharmacologyNot in File18211830FASEB J.218The FASEB JournalFASEB J.1163. High levels of mRNA of both apelin and its GPCR APJ are found in cardiac myocytes, vascular smooth muscle cells and endothelial cells. It has been proposed as a new therapeutic target, but more research is warranted on its exact mode of action ADDIN REFMGR.CITE Ronkainen2007556Hypoxia inducible factor regulates the cardiac expression and secretion of apelinJournal556Hypoxia inducible factor regulates the cardiac expression and secretion of apelinRonkainen,V.P.Ronkainen,J.J.Hanninen,S.L.Leskinen,H.Ruas,J.L.Pereira,T.Poellinger,L.Vuolteenaho,O.Tavi,P.2007/3/6bloodBlood PressureGene ExpressionHIF-1alphahypoxiaischemiamodelMyocardial InfarctionMyocardiumOxygenPeptidespharmacologyNot in File18211830FASEB J.218The FASEB JournalFASEB J.1163.
Growth hormones and the PI3K/Akt1 pathway
Growth hormone (GH) and insulin-like growth hormone (IGF-1, secreted by the liver in response to GH) play a role in cardiac development and the maintenance of its structure and function. There is a high incidence of concentric cardiomyopathy in acromegalic patients ADDIN REFMGR.CITE Lopez-Velasco1997401Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic hypertension?Journal401Cardiac involvement in acromegaly: specific myocardiopathy or consequence of systemic hypertension?Lopez-Velasco,R.Escobar-Morreale,H.F.Vega,B.Villa,E.Sancho,J.M.Moya-Mur,J.L.Garcia-Robles,R.1997/4AcromegalyheartInsulin-Like Growth Factor Iheart failurehypertrophyNot in File10471053J.Clin.Endocrinol.Metab.824J.Clin.Endocrinol.Metab.1164 and cardiac function improves when patients with GH deficiency are treated with GH ADDIN REFMGR.CITE Maison2003400Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysisJournal400Cardiac effects of growth hormone in adults with growth hormone deficiency: a meta-analysisMaison,P.Chanson,P.2003/11/25Growth HormoneheartHypopituitarismheart failureNot in File26482652Circulation.10821Circulation.1165. IGF-I directly causes cardiomyocyte hypertrophy in rats, ADDIN REFMGR.CITE Ito1993402Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytesJournal402Insulin-like growth factor-I induces hypertrophy with enhanced expression of muscle specific genes in cultured rat cardiomyocytesIto,H.Hiroe,M.Hirata,Y.Tsujino,M.Adachi,S.Shichiri,M.Koike,A.Nogami,A.Marumo,F.1993/5ActinsGrowth HormoneInsulin-Like Growth Factor IMyocardiumheart failurehypertrophyNot in File17151721Circulation.875Circulation.1166 is involved in myofilament calcium sensitization ADDIN REFMGR.CITE Cittadini1998403Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated musclesJournal403Insulin-like growth factor-1 but not growth hormone augments mammalian myocardial contractility by sensitizing the myofilament to Ca2+ through a wortmannin-sensitive pathway: studies in rat and ferret isolated musclesCittadini,A.Ishiguro,Y.Stromer,H.Spindler,M.Moses,A.C.Clark,R.Douglas,P.S.Ingwall,J.S.Morgan,J.P.1998/7/13calciumcontractilityGrowth HormoneheartInsulin-Like Growth Factor IMicrofilamentsNOheart failureNot in File5059Circ.Res.831Circ.Res.1167 and inhibits apoptosis ADDIN REFMGR.CITE Chen2000404Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytesJournal404Insulin-like growth factor I retards apoptotic signaling induced by ethanol in cardiomyocytesChen,D.B.Wang,L.Wang,P.H.2000/8/251-Phosphatidylinositol 3-Kinaseapoptosisbcl-2-Associated X ProteinCaspase 3Caspasesheartheart failureInsulin-Like Growth Factor IProto-Oncogene Proteins c-bcl-2Not in File16831693Life Sci.6714Life Sci.1168.
An important signaling pathway of IGF-1 is the PI3K/Akt1 pathway (see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%203.ppt"fig. 3). The same pathway is also used by insulin, cardiotropin-1 (CT-1) and PDGF. Binding of these ligands to their m e m b r a n e R T K a c t i v a t e s P I 3 K ( s u b t y p e p 1 1 0 ) . P I 3 K p h o s p h o r y l a t e s t h e m e m b r a n e p h o s p h o l i p i d p h o s p h a t i d y l i n o s i t o l - 4 , 5 - b i p h o s p h a t e ( P I P 2 ) , w h i c h l e a d s t o t h e f o r m a t i o n o f p h o s p h a t y l i n o s i t o l - 3 , 4 , 5 - t r i p h o s p h a t e ( P I P 3 ) a n d r e c r u i t m e n t o f t h e p r o t e i n k i n a s e A k t 1 (also known as PKB) to the cell membrane together with its activator PDK1. After activation of Akt1, signaling events are induced that are associated with normal myocardial growth, physiological hypertrophy and prevention of cellular senescence ADDIN REFMGR.CITE Dorn2005442Protein kinase cascades in the regulation of cardiac hypertrophyJournal442Protein kinase cascades in the regulation of cardiac hypertrophyDorn,G.W.Force,T.2005/31-Phosphatidylinositol 3-KinaseAnimalsbiosynthesiscalciumCardiomegalyenzymologygeneticsGlycogen Synthase KinasesGTP-Binding Protein alpha Subunits,Gq-G11heartHumanshypertrophyIsoenzymesmetabolismmodelMyocardial ContractionMyocardiumpathologyphysiologyphysiopathologyProtein Kinase CProtein KinasesProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktreviewSignal TransductionNot in File527537J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1Torella2004615Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpressionJournal615Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpressionTorella,D.Rota,M.Nurzynska,D.Musso,E.Monsen,A.Shiraishi,I.Zias,E.Walsh,K.Rosenzweig,A.Sussman,M.A.Urbanek,K.Nadal-Ginard,B.Kajstura,J.Anversa,P.Leri,A.2004/3/5AgingAnimalsapoptosisBiological MarkersCardiomyopathiesCell AgingCell CountCell Cycle ProteinsCell DeathCell DifferentiationCell DivisionCell LineageCyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent Kinase Inhibitor p27CyclinscytologyDnaDNA Damagegeneticsheartheart failureHumansInsulin-Like Growth Factor IMalemetabolismMiceMice,TransgenicMultipotent Stem CellsMyocytes,CardiacOxidative StresspathologyPhosphorylationphysiologyProtein Processing,Post-TranslationalProtein-Serine-Threonine KinasesProteinsProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRecombinant Fusion ProteinsRegenerationResearchsurvivalTelomeraseTelomereTumor Suppressor Protein p14ARFTumor Suppressor Protein p53Tumor Suppressor ProteinsultrastructureNot in File514524Circ.Res.944Circ.Res.184;169. The PI3K/Akt1 pathway is inhibited by PTEN (phosphatase and tensin homolog on chromosome 10), which is a tumor-suppressor phosphatase that dephosphorylates PIP3 and therefore prevents Akt1 activation ADDIN REFMGR.CITE Crackower2002443Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathwaysJournal443Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathwaysCrackower,M.A.Oudit,G.Y.Kozieradzki,I.Sarao,R.Sun,H.Sasaki,T.Hirsch,E.Suzuki,A.Shioi,T.Irie-Sasaki,J.Sah,R.Cheng,H.Y.Rybin,V.O.Lembo,G.Fratta,L.Oliveira-dos-Santos,A.J.Benovic,J.L.Kahn,C.R.Izumo,S.Steinberg,S.F.Wymann,M.P.Backx,P.H.Penninger,J.M.2002/91-Phosphatidylinositol 3-KinaseAdrenergic beta-AgonistsanalysisAnimalsCardiomegalyCell SizeCells,CulturedchemistrycontractilityCyclic AMPDose-Response Relationship,DrugEthanolaminesGene Expression RegulationGenes,Tumor SuppressorgeneticsGPCRGTP-Binding ProteinshearthypertrophymetabolismMiceMice,Mutant StrainsMice,TransgenicmuscleMyocardial ContractionMyocardiumpharmacologyPhosphoric Monoester HydrolasesPhosphorylationphysiopathologyProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseSignal TransductionTumor Suppressor ProteinsNot in File737749Cell.1106Cell.1170.
After activation of Akt1 the mammalian target of rapamycin (mTOR) is activated and GSK-3 is inhibited. mTOR is a central signaling molecule for hypertrophy-associated protein synthesis. mTOR can be up-regulated by a second -Akt1 independent- way through the activation of the ERK1/2 pathway by GPCRs. GSK-3 is a negative regulator of both normal and pathologic stress-induced growth ADDIN REFMGR.CITE Michael2004444Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heartJournal444Glycogen synthase kinase-3beta regulates growth, calcium homeostasis, and diastolic function in the heartMichael,A.Haq,S.Chen,X.Hsich,E.Cui,L.Walters,B.Shao,Z.Bhattacharya,K.Kilter,H.Huggins,G.Andreucci,M.Periasamy,M.Solomon,R.N.Liao,R.Patten,R.Molkentin,J.D.Force,T.2004/5/14AnimalscalciumCalcium-Transporting ATPasesDiastolediastolic functionFemaleGene Expression Regulation,EnzymologicgeneticsGlycogen Synthase Kinase 3growth & developmentheartheart failureHomeostasishypertrophymetabolismMiceMice,TransgenicMuscle CellsPhenotypephysiologyPromoter Regions (Genetics)Recombinant ProteinsSarcoplasmic ReticulumSarcoplasmic Reticulum Calcium-Transporting ATPasesSystoletherapyNot in File2138321393J.Biol.Chem.27920Journal of Biological ChemistryJ.Biol.Chem.1Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.137;171. Induction of the PI3K/Akt1 pathway releases the cellular protein synthesis machinery from its tonic inhibition by GSK-3. Examples of hypertrophic growth regulating transcription factors that are normally inhibited by GSK-3 are c-Myc, GATA-4 and NFAT (see above for the link with calcineurin signaling) ADDIN REFMGR.CITE Dorn2005442Protein kinase cascades in the regulation of cardiac hypertrophyJournal442Protein kinase cascades in the regulation of cardiac hypertrophyDorn,G.W.Force,T.2005/31-Phosphatidylinositol 3-KinaseAnimalsbiosynthesiscalciumCardiomegalyenzymologygeneticsGlycogen Synthase KinasesGTP-Binding Protein alpha Subunits,Gq-G11heartHumanshypertrophyIsoenzymesmetabolismmodelMyocardial ContractionMyocardiumpathologyphysiologyphysiopathologyProtein Kinase CProtein KinasesProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktreviewSignal TransductionNot in File527537J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.184. Transgenic mice that express a constitutively active form of GSK-3 under control of a cardiac-specific promoter are physiologically normal under n o n s t r e s s e d c o n d i t i o n s , b u t h a v e a d i m i n i s h e d h y p e r t r o p h i c r e s p o n s e t o c h r o n i c - a d r e n e r g i c s t i m u l a t i o n a n d p r e s s u r e o v e r l o a d . R e m a r k a b l y , s y s t o l i c f u n c t i o n i n t h e s e c i r c u m s t a n c e s w a s u n a f f e c t e d d e s p i t e t h e a b s e n c e o f h y p e r t r o p h y A D D I N R E F M G R . C I T E < R e f m an>Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.137. It should be noted that GATA-4 provides a substrate for the anti-apoptotic aspects of Akt1 signaling, since this transcription factor upregulates the survival factor Bcl3 ADDIN REFMGR.CITE Kobayashi2006447Transcription factor gata4 regulates cardiac BCL2 gene expression in vitro and in vivoJournal447Transcription factor gata4 regulates cardiac BCL2 gene expression in vitro and in vivoKobayashi,S.Lackey,T.Huang,Y.Bisping,E.Pu,W.T.Boxer,L.M.Liang,Q.2006/4analysisAnimalsAntibiotics,Antineoplasticbcl-X ProteinCells,CulturedDoxorubicindrug effectsGATA4 Transcription FactorGene ExpressionGene Expression RegulationgeneticsheartHumansmetabolismMiceMice,TransgenicMyocytes,CardiacpharmacologyPlasmidsProto-Oncogene Proteins c-bcl-2RatsRats,Sprague-DawleyTransfectionNot in File800802FASEB J.206The FASEB Journal F A S E B J . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 7 2 . T h e r e a r e , h o w e v e r , m a n y o t h e r w a y s i n w h i c h A k t 1 a c t s a s a p r o - s u r v i v a l f a c t o r ( a c t i v a t i o n o f B a d , I K K , F o x o 3 a a n d p r o c a s p a s e - 9 ) A D D I N R E F M G R . C I T E < R efman>Foo2005461Death begets failure in the heartJournal461Death begets failure in the heartFoo,R.S.Mani,K.Kitsis,R.N.2005/3AnimalsapoptosisCardiac Output,LowCell Deathcytologyheartheart failureHumansmetabolismmodelMyocytes,CardiacpathologyphysiologyreviewSignal TransductiontherapyNot in File565571J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1173.
Binding of ATII, catecholamines and ET-1 to their GPCR is associated with a similar pathway, involving Akt1 and another PI3K s u b t y p e ( p 1 1 0 ) . W h i l e a c t i v a t i o n o f A k t 1 t h r o u g h p 1 1 0 i s c o n s i d e r e d a b e n e f i c i a l r e s p o n s e , a c t i v a t i o n t h r o u g h p 1 1 0 i s a s s o c i a t e d w i t h m a l a d a p t i v e h y p e r t r o p h y . S i n c e t h i s t y p e o f A k t 1 a c t i v a t i o n i s a s s o c i a t e d w i t h t h e s a m e i n d u c t i o n o f m T O R a n d i n h i b i t i o n o f G S K - 3 , i t i s l i k e l y t h a t o t h e r d e t r i m e n t a l e f f e c t s o f p 1 1 0 s i g n a l i n g s u c h a s t h e a c t i v a t i o n o f - A R K a n d a d e c r e a s e d c a p i l l a r y d e n s i t y a r e r e s p o n s i b l e A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > P e r r i n o < / A u t h o r > < Y e a r > 2 0 0 6 < / Y e a r > < R e c N u m > 4 7 0 < / R e c N u m > < I D T e xt>Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionJournal470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionPerrino,C.Naga Prasad,S.V.Mao,L.Noma,T.Yan,Z.Kim,H.S.Smithies,O.Rockman,H.A.2006/61-Phosphatidylinositol 3-KinaseAdrenergic beta-AntagonistsAnimalsantagonists & inhibitorsbeta-Adrenergic Receptor KinaseBlood PressureBlood VesselsCardiac Output,LowCardiomegalyCells,CulturedcytologyechocardiographyexerciseFemaleGene ExpressionGene Expression RegulationgeneticsheartHemodynamic ProcessesHumansHypertensionhypertrophyHypertrophy,Left VentricularmetabolismMetoprololMiceMice,Inbred C57BLMice,TransgenicMyocardiumpathologyPhenotypephysiologyphysiopathologyReceptors,Adrenergic,betaSignal TransductionStressNot in File15471560J.Clin.Invest.1166Journal of Clinical InvestigationJ.Clin.Invest.1Dorn2005442Protein kinase cascades in the regulation of cardiac hypertrophyJournal442Protein kinase cascades in the regulation of cardiac hypertrophyDorn,G.W.Force,T.2005/31-Phosphatidylinositol 3-KinaseAnimalsbiosynthesiscalciumCardiomegalyenzymologygeneticsGlycogen Synthase KinasesGTP-Binding Protein alpha Subunits,Gq-G11heartHumanshypertrophyIsoenzymesmetabolismmodelMyocardial ContractionMyocardiumpathologyphysiologyphysiopathologyProtein Kinase CProtein KinasesProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktreviewSignal TransductionNot in File527537J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1Shiojima2005570Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failureJournal570Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failureShiojima,I.Sato,K.Izumiya,Y.Schiekofer,S.Ito,M.Liao,R.Colucci,W.S.Walsh,K.2005/8Angiopoietin-2AnimalsbiosynthesisCapillariesCardiologyCardiomyopathiesCardiomyopathy,DilatedcontractilityenzymologyGene Expression Regulationgeneticsgrowth & developmentheartheart failureHeart Failure,CongestiveHumanshypertrophymetabolismMiceMice,TransgenicMyocardiumNeovascularization,PathologicpathologyProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktremodelingVascular Endothelial Growth Factor AVEGFVentricular RemodelingNot in File21082118J.Clin.Invest.1158Journal of Clinical InvestigationJ.Clin.Invest.143;84;174. Not only the trigger, but also the duration of Akt1 stimulation seems to determine whether adaptive or maladaptive hypertrophy (with reduced capillarization) follows ADDIN REFMGR.CITE Shiojima2005570Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failureJournal570Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failureShiojima,I.Sato,K.Izumiya,Y.Schiekofer,S.Ito,M.Liao,R.Colucci,W.S.Walsh,K.2005/8Angiopoietin-2AnimalsbiosynthesisCapillariesCardiologyCardiomyopathiesCardiomyopathy,DilatedcontractilityenzymologyGene Expression Regulationgeneticsgrowth & developmentheartheart failureHeart Failure,CongestiveHumanshypertrophymetabolismMiceMice,TransgenicMyocardiumNeovascularization,PathologicpathologyProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktremodelingVascular Endothelial Growth Factor AVEGFVentricular RemodelingNot in File21082118J.Clin.Invest.1158Jou r n a l o f C l i n i c a l I n v e s t i g a t i o n < / f > < / Z Z _ J o u r n a l F u l l > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > J . C l i n . I n v e s t . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 7 4 .
p 5 3 a n d S i r 2
L V a n d R V p r e s s u r e o v e r l o a d a r e a s s o c i a t e d w i t h a c c u m u l a t i o n o f t h e t u m o r s u p p r e s s o r g e n e p 5 3 a n d s u b s e q u e n t s u p p r e s s i o n o f H I F - 1 a n d a n g i o g e n i c g r o w t h f a c t o r s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > I k e d a < / A u t h o r > < Y e a r > 1 9 9 9 < / Y e a r > < R e c N u m > 6 4 7 < / R e c N u m > < I D T e x t > C a r d i o m y o c y t e a p o p t o s i s w i t h e n h a n c e d e x p r e ssion of P53 and Bax in right ventricle after pulmonary arterial bandingJournal647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingIkeda,S.Hamada,M.Hiwada,K.1999analysisAnimalsapoptosisbcl-2-Associated X ProteinBody WeightConstrictioncytologyDNA FragmentationGenes,p53geneticsHeart VentriclesHypertrophy,Right VentricularImmunohistochemistryIn Situ Nick-End LabelingMalemetabolismMyocardiumphysiologyPressureProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRatsRats,Sprague-Dawleyright ventricleRNA,MessengersurgeryTime FactorsTumor Suppressor Protein p53Up-RegulationVentricular PressureNot in File925933Life Sci.659Life Sci.1Sano2007523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadJournal523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadSano,M.Minamino,T.Toko,H.Miyauchi,H.Orimo,M.Qin,Y.Akazawa,H.Tateno,K.Kayama,Y.Harada,M.Shimizu,I.Asahara,T.Hamada,H.Tomita,S.Molkentin,J.D.Zou,Y.Komuro,I.2007/3/22Animalsantagonists & inhibitorsAortaBlood PressureCardiac Output,LowCardiomegalyCoronary CirculationDisease Progressiongeneticsheartheart failurehypertrophyHypoxia-Inducible Factor 1,alpha SubunitmetabolismMiceNeovascularization,PathologicpathologyphysiopathologyTumor Suppressor Protein p53Not in File444448Nature.4467134Nature.127;50. p53 induces apoptosis of cells with DNA damage via activation of Bax and via direct, transcription independent, induction of the mitochondrial death pathway ADDIN REFMGR.CITE Levine1997517p53, the cellular gatekeeper for growth and divisionJournal517p53, the cellular gatekeeper for growth and divisionLevine,A.J.1997/2/7AnimalsCell CycleCell DivisionchemistryGenes,p53geneticsHumansphysiologyStructure-Activity RelationshipTumor Suppressor Protein p53Not in File323331Cell.883Cell.1Regula2001534p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcriptionJournal534p53 activates the mitochondrial death pathway and apoptosis of ventricular myocytes independent of de novo gene transcriptionRegula,K.M.Kirshenbaum,L.A.2001/8AdenoviridaeanalysisAnimalsAnimals,Newbornantagonists & inhibitorsapoptosisCaspase 3CaspasesCysteine Proteinase InhibitorsCytochrome c GroupcytologyDnaElectrophoresisGene Expression RegulationGenes,p53Genes,ReporterGenetic VectorsgeneticsHeart VentriclesHumansmetabolismmitochondriaMitochondria,HeartMyocardiumOligopeptidespathologypharmacologyphysiologyPromoter Regions (Genetics)Proto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2RatsRats,Sprague-DawleyResearchTranscription,GeneticTransfectionNot in File14351445J.Mol.Cell Cardiol.338J.Mol.Cell Cardiol. < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 7 5 ; 1 7 6 . p 5 3 d e p e n d e n t a p o p t o s i s i s s u p p r e s s e d b y s i l e n t i n f o r m a t i o n r e g u l a t o r 2 ( S i r 2 ) , w h i c h a l s o f u n c t i o n s a s a H D A C A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > L u o < / A u t h o r > < Y e a r > 2 0 0 1 < /Year>516Negative control of p53 by Sir2alpha promotes cell survival under stressJournal516Negative control of p53 by Sir2alpha promotes cell survival under stressLuo,J.Nikolaev,A.Y.Imai,S.Chen,D.Su,F.Shiloh,A.Guarente,L.Gu,W.2001/10AgingAnimalsAntigens,CD95apoptosisbiosynthesisBlotting,WesternCell DeathCell LineCell SurvivalDnaDNA DamageDNA,ComplementaryDose-Response Relationship,DrugElectrophoresis,Polyacrylamide GelgeneticsHistone DeacetylasesHumansmetabolismMiceMutagenesis,Site-DirectedNadNeoplasmsNiacinamideOxidative StresspathologypharmacologyPoint MutationPoly(ADP-ribose) PolymerasesPolymerase Chain ReactionProtein BindingProtein Structure,TertiarySirtuinsStresssurvivaltherapyTrans-Activation (Genetics)Trans-ActivatorsTumor Suppressor Protein p53Not in File137 < E n d _ P a g e > 1 4 8 < / E n d _ P a g e > < P e r i o d i c a l > C e l l . < / P e r i o d i c a l > < V o l u m e > 1 0 7 < / V o l u m e > < I s s u e > 2 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > C e l l . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 7 7 . S i r 2 e x p r e s s i o n i s i n c r e a s e d in heart failure and has been shown to inhibit apoptosis in cultured cardiomyocytes, thereby providing some endogenous counterbalancing effect ADDIN REFMGR.CITE Alcendor2004533Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytesJournal533Silent information regulator 2alpha, a longevity factor and class III histone deacetylase, is an essential endogenous apoptosis inhibitor in cardiac myocytesAlcendor,R.R.Kirshenbaum,L.A.Imai,S.Vatner,S.F.Sadoshima,J.2004/11/12AcetylationAlkaloidsAnimalsantagonists & inhibitorsapoptosisAtrial Natriuretic FactorBenzamidesBenzophenanthridinesbiosynthesisCaspase 3Cell DeathCell NucleusCell SizeCell SurvivalCells,CulturedCulture Media,Serum-FreeCysteine Proteinase InhibitorscytologyDnaDNA DamageDogsdrug effectsenzymologyGene SilencingGenes,DominantGenes,p53geneticsheartheart failureHeart Failure,CongestiveHeart VentriclesHydroxamic AcidshypertrophyHypertrophy,Left VentricularLongevitymetabolismMiceMyocytes,CardiacNaphtholsNiacinamidepathologypharmacologyPhenanthridinesphysiologyProtein Processing,Post-TranslationalRatsRats,WistarRecombinant Fusion ProteinsResearchSirtuinssurvivalTranscription,GeneticTumor Suppressor Protein p53Not in File971980Circ.Res.9510Circ.Res.1178. The effect of p53 upregulation on myocardial capillary density in hypertrophic hearts will be discussed below.
Platelet derived growth factor
PDGF has been implicated in the pathobiology of pulmonary vascular remodeling in PAH ADDIN REFMGR.CITE Schermuly2005242Reversal of experimental pulmonary hypertension by PDGF inhibitionJournal242Reversal of experimental pulmonary hypertension by PDGF inhibitionSchermuly,Ralph TheoDony,EvaGhofrani,Hossein ArdeschirPullamsetti,SoniSavai,RajkumarRoth,MarkusSydykov,AkylbekLai,Ying JuWeissmann,NorbertSeeger,WernerGrimminger,Friedrich2005/10/1imatinibPDGFpulmonary hypertensionNot in File28112821J.Clin.Invest.11510http://www.jci.org/cgi/content/abstract/115/10/2811Journal of Clinical InvestigationJ.Clin.Invest.19. The same molecule has been attributed with cardio-protective effects in models of myocardial infarction ADDIN REFMGR.CITE Edelberg2002587Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heartJournal587Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heartEdelberg,J.M.LEE,S.H.Kaur,M.Tang,L.Feirt,N.M.McCabe,S.Bramwell,O.Wong,S.C.Hong,M.K.2002/2/5Age FactorsAgingAnimalsAnimals,NewbornbiosynthesisCells,CulturedclinicalCoculture TechniquesCoronary VesselscytologyDisease Models,Animaldrug effectsEndothelial CellsEndothelium,VasculargeneticsGraft SurvivalheartHeart TransplantationLigationmetabolismmethodsMiceMice,Inbred C57BLmodelMyocardial InfarctionMyocardiumNeovascularization,PhysiologicpathologyPDGFpharmacologyPhenotypephysiologyPlatelet-Derived Growth Factorprevention & controlProto-Oncogene Proteins c-sisRatsReverse Transcriptase Polymerase Chain ReactiontherapyNot in File608613Circulation.1055Circulation.1Hsieh2006588Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicityJournal588Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicityHsieh,P.C.MacGillivray,C.Gannon,J.Cruz,F.U.Lee,R.T.2006/8/15administration & dosageadverse effectsAnimalschemically inducedDrug Delivery Systemsdrug effectsdrug therapyechocardiographyheartheart failureHemodynamic ProcessesHypertensionHypertension,PulmonaryInjectionsLungMalemethodsMyocardial InfarctionMyocardiumNanotechnologyNOPDGFpharmacologyphysiologyphysiopathologyPlatelet-Derived Growth Factorprevention & controlPulmonary Arterypulmonary hypertensionRandom AllocationRatsRats,Sprague-DawleyRegional Blood FlowsurgerytherapytoxicityVentricular FunctionNot in File637644Circulation.1147Circulation.164;65. The proposed explanations are enhanced cardiomyocyte survival in the early period after acute infarction, anti-inflammatory effects and potential activation of progenitor cells (either resident or bone-marrow derived), which may differentiate into cardiomyocytes and coronary vessels ADDIN REFMGR.CITE Tang2005589The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- miceJournal589The absence of platelet-derived growth factor-B in circulating cells promotes immune and inflammatory responses in atherosclerosis-prone ApoE-/- miceTang,J.Kozaki,K.Farr,A.G.Martin,P.J.Lindahl,P.Betsholtz,C.Raines,E.W.2005/9AnimalsApolipoproteins EArteriosclerosisBlood CellsBone Marrow CellsCarrier ProteinsChimeracomplicationsdeficiencyetiologyGene Expression ProfilingGenetic Predisposition to DiseasegeneticsimmunologyinflammationLigandsLymphocyte ActivationMacrophagesMalemetabolismMiceMice,Inbred C57BLMice,KnockoutMonocytesmuscleMuscle CellspathologyPDGFPhenotypePlatelet-Derived Growth FactorProto-Oncogene Proteins c-sisReceptor,Platelet-Derived Growth Factor alphaRepressor ProteinsRNA,MessengerSuppressor of Cytokine Signaling ProteinsT-LymphocytesTranscription FactorsVascular DiseasesNot in File901912Am.J.Pathol.1673Am.J.Pathol.1Xaymardan2004590Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytesJournal590Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytesXaymardan,M.Tang,L.Zagreda,L.Pallante,B.Zheng,J.Chazen,J.L.Chin,A.Duignan,I.Nahirney,P.Rafii,S.Mikawa,T.Edelberg,J.M.2004/3AdultAnimalsbiosynthesisBone Marrow CellsBone Marrow TransplantationCell DifferentiationComputer Systemscytologydrug effectsdrug therapyechocardiographyexerciseExercise TestFibroblast Growth Factor 2geneticsheartInjectionsKineticsMesenchymal Stem Cell TransplantationMesenchymal Stem CellsMiceMice,Inbred BALB CMice,Inbred C57BLMicroscopy,VideomodelMyocardial InfarctionMyocytes,CardiacNOpathologypharmacologyphysiologyPlatelet-Derived Growth FactorRatsRats,Inbred F344RNA,MessengerStem Cellstherapeutic usetherapyultrasonographyVascular Endothelial Growth Factor ANot in FileE39E45Circ.Res.945Circ.Res.1Beltrami2003591Adult cardiac stem cells are multipotent and support myocardial regenerationJournal591Adult cardiac stem cells are multipotent and support myocardial regenerationBeltrami,A.P.Barlucchi,L.Torella,D.Baker,M.Limana,F.Chimenti,S.Kasahara,H.Rota,M.Musso,E.Urbanek,K.Leri,A.Kajstura,J.Nadal-Ginard,B.Anversa,P.2003/9AdultAnimalsBiological MarkersBlood VesselsCell DifferentiationCell LineageCells,CulturedClone CellscytologyEndothelial CellsEndothelium,VascularFemalegeneticsgrowth & developmentheartmetabolismMultipotent Stem CellsmuscleMyocardial InfarctionMyocardiumMyocytes,CardiacMyocytes,Smooth MusclephysiologyProto-Oncogene Proteins c-kitRatsRats,Inbred F344RegenerationResearchStem CellstherapytransplantationNot in File763776Cell.1146Cell.1179-181. Active PDGF is built up by polypeptides (A and B chain) that form homo- or heterodimers and st i m u l a t e a n d c e l l s u r f a c e r e c e p t o r s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > H e l d i n < / A u t h o r > < Y e a r > 1 9 9 9 < / Y e a r > < R e c N u m > 5 9 2 < / R e c N u m > < I D T e x t > M e c h a n i s m o f A c t i o n a n d I n V i v o R o l e o f P l a t e l e t - D e r i v e d G r o w t h F a c t o r < / I D T e x t > < M D L R e f _ T y p e = " J o u r n a l " > < R e f _ T y p e > J o urnal592Mechanism of Action and In Vivo Role of Platelet-Derived Growth FactorHeldin,Carl HenrikWestermark,Bengt1999/10/1Cell MovementCell ProliferationEmbryonic DevelopmentPDGFPlatelet-Derived Growth FactorreviewTyrosineWound HealingNot in File12831316Physiol.Rev.794http://physrev.physiology.org/cgi/content/abstract/79/4/1283Physiological ReviewsPhysiol.Rev.1182. PDGF receptors belong to a family of transmembrane RTKs. When the RTK binds with PDGF, it is autophosphorylated and subsequently activates different signaling pathways, e.g. PI3K, MAPK and signal transducer and activator of transcription 3 (STAT-3) ADDIN REFMGR.CITE Heldin1999592Mechanism of Action and In Vivo Role of Platelet-Derived Growth FactorJournal592Mechanism of Action and In Vivo Role of Platelet-Derived Growth FactorHeldin,Carl HenrikWestermark,Bengt1999/10/1Cell MovementCell ProliferationEmbryonic DevelopmentPDGFPlatelet-Derived Growth FactorreviewTyrosineWound HealingNot in File12831316Physiol.Rev.794http://physrev.physiology.org/cgi/content/abstract/79/4/1283Physiological ReviewsPhysiol.Rev.1182.
gp130 signaling cytokines
Leukemia inhibitory factor (LIF) and CT-1 are cytokines that induce hypertrophic growth and suppress apoptosis via gp130 receptors ADDIN REFMGR.CITE Hirota1999415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressJournal415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressHirota,H.Chen,J.Betz,U.A.Rajewsky,K.Gu,Y.Ross,J.,Jr.Muller,W.Chien,K.R.1999/4/16AnimalsAntigens,CDapoptosisBiomechanicsCardiomegalyCardiomyopathiesCell SurvivalCytokine Receptor gp130CytokinesembryologyetiologyFetal HeartGene Expression Regulation,Developmentalgeneticsgp130heartheart failureHeart Failure,CongestivehypertrophyMembrane GlycoproteinsMiceMice,KnockoutmuscleMyocardiumpathologyphysiologyphysiopathologyReceptors,CytokinesurvivalNot in File189198Cell.972Cell.1Wollert1997406Cardiotrophin-1 and the role of gp130-dependent signaling pathways in cardiac growth and developmentJournal406Cardiotrophin-1 and the role of gp130-dependent signaling pathways in cardiac growth and developmentWollert,K.C.Chien,K.R.1997/7Cytokinesgp130heart failurehypertrophyIL-6MyocardiumNot in File492501J.Mol.Med.757J.Mol.Med.132;183. Whereas stimulation of GPCRs generally induces hypertrophy through parallel assembly of additional sarcomeres, stimulation of gp130 receptors results in assembly of sarcomeres in series. The former results in an increase in myocyte width, the latter in an increase in myocyte length ADDIN REFMGR.CITE Wollert1996407Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathwaysJournal407Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathwaysWollert,K.C.Taga,T.Saito,M.Narazaki,M.Kishimoto,T.Glembotski,C.C.Vernallis,A.B.Heath,J.K.Pennica,D.Wood,W.I.Chien,K.R.1996/4/19ActinsAtrial Natriuretic FactorCT-1Cytokinesheartheart failurehypertrophyInterleukin-6Leukemia Inhibitory FactorMyocardiumsarcomereNot in File95359545J.Biol.Chem.27116Journal of Biological ChemistryJ.Biol.Chem.1184. It remains to be determined whether this implies that gp130 signaling cytokines are predominantly involved in remodeling after volume overload (which is known to be associated with serial sarcomere assembly, in contrast to pressure overload), or whether the activation of these cytokines signifies maladaptive remodeling, i.e. pathologic dilatation ADDIN REFMGR.CITE Hirota1999415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressJournal415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressHirota,H.Chen,J.Betz,U.A.Rajewsky,K.Gu,Y.Ross,J.,Jr.Muller,W.Chien,K.R.1999/4/16AnimalsAntigens,CDapoptosisBiomechanicsCardiomegalyCardiomyopathiesCell SurvivalCytokine Receptor gp130CytokinesembryologyetiologyFetal HeartGene Expression Regulation,Developmentalgeneticsgp130heartheart failureHeart Failure,CongestivehypertrophyMembrane GlycoproteinsMiceMice,KnockoutmuscleMyocardiumpathologyphysiologyphysiopathologyReceptors,CytokinesurvivalNot in File189198Cell.972Cell.132. LIF and CT-1 are also involved in cardiac remodeling after ischemia and have been shown to stimulate angiogenesis, fibroblast migration and collagen synthesis in this context ADDIN REFMGR.CITE Freed2005408Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heartJournal408Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heartFreed,D.H.Cunnington,R.H.Dangerfield,A.L.Sutton,J.S.Dixon,I.M.2005/3/1CollagenCytokinesfibroblastfibrosisheartheart failurehypertrophyIL-6ischemiaMyocardial InfarctionMyocardiumCT-1Not in File782792Cardiovasc.Res.654Cardiovasc.Res.1185. It is unclear whether the net result of gp130 signaling in the overloaded human heart is beneficial or detrimental. The anti-apoptotic effect of gp130 signaling involve both activation of ERK1/2 and activation of Akt1 ADDIN REFMGR.CITE Sheng1997530Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophyJournal530Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophySheng,Z.Knowlton,K.Chen,J.Hoshijima,M.Brown,J.H.Chien,K.R.1997/2/28AnimalsapoptosisCa(2+)-Calmodulin Dependent Protein KinaseCT-1CytokinescytologyDNA FragmentationDNA-Binding Proteinsdrug effectsEnzyme InhibitorsFlavonoidsgeneticshearthypertrophyInterleukin-6MAP Kinase Kinase 1metabolismMiceMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase KinasesmuscleMuscle CellsMutagenesisMyocardiumpharmacologyProtein-Serine-Threonine KinasesProtein-Tyrosine KinasesRatsSTAT3 Transcription FactorsurvivalTrans-ActivatorsTransfectionNot in File57835791J.Biol.Chem.2729Journal of Biological ChemistryJ.Biol.Chem.1Oh1998531Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytesJournal531Activation of phosphatidylinositol 3-kinase through glycoprotein 130 induces protein kinase B and p70 S6 kinase phosphorylation in cardiac myocytesOh,H.Fujio,Y.Kunisada,K.Hirota,H.Matsui,H.Kishimoto,T.Yamauchi-Takihara,K.1998/4/171-Phosphatidylinositol 3-KinaseAndrostadienesAnimalsAnimals,NewbornAntigens,CDbiosynthesisCells,CulturedCytokine Receptor gp130cytologyDNA-Binding Proteinsdrug effectsEnzyme ActivationEnzyme InhibitorsenzymologyGenes,fosgp130Growth InhibitorsInterleukin-6Janus Kinase 1KineticsLeukemia Inhibitory FactorLymphokinesMembrane GlycoproteinsmetabolismMyocardiumpharmacologyPhosphorylationProtein-Serine-Threonine KinasesProtein-Tyrosine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-fosRatsRats,Sprague-DawleyRecombinant ProteinsRibosomal Protein S6 KinasesSignal TransductionSTAT3 Transcription FactorTrans-ActivatorsTranscription,GeneticNot in File97039710J.Biol.Chem.27316Journal of Biological ChemistryJ.Biol.Chem.1186;187.
Upon stimulation of the gp130 receptor, JAKs are phosphorylated; this is associated with the activation of multiple intracellular signaling pathways (PI3K, MAPKs, STAT-3, and Src) ADDIN REFMGR.CITE Freed2005408Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heartJournal408Emerging evidence for the role of cardiotrophin-1 in cardiac repair in the infarcted heartFreed,D.H.Cunnington,R.H.Dangerfield,A.L.Sutton,J.S.Dixon,I.M.2005/3/1CollagenCytokinesfibroblastfibrosisheartheart failurehypertrophyIL-6ischemiaMyocardial InfarctionMyocardiumCT-1Not in File782792Cardiovasc.Res.654Cardiovasc.Res.1185. STAT-3 is a transcription factor that directs a wide variety of biologic processes, such as cell survival and apoptosis, inflammation, angiogenesis, and cardiac hypertrophy ADDIN REFMGR.CITE Hilfiker-Kleiner2005572STAT3-mediated activation of myocardial capillary growthJournal572STAT3-mediated activation of myocardial capillary growthHilfiker-Kleiner,D.Limbourg,A.Drexler,H.2005/5AdultAnimalsCapillariesCardiac Output,LowCardiologyCoronary VesselsCytokinesdrug therapyembryologyEmbryonic DevelopmentEndothelial Cellsfibrosisgeneticsgrowth & developmentheartheart failureHomeostasisHumansmetabolismMicrocirculationNeovascularization,PathologicNeovascularization,PhysiologicOxygenPerfusionphysiologyphysiopathologyreviewSTAT3 Transcription FactorStresssurvivalVEGFNot in File152157Trends Cardiovasc.Med.154Trends Cardiovasc.Med.1188. In the heart, its activation primarily follows that of phosphorylation at tyrosine 705 by JAK-1, which occurs upon binding of ligand to gp130 receptors. In fact, the JAK-STAT-3 signaling pathway has been shown to mediate most hypertrophic and cyto-protective effects of gp130 activation in cardiomyocytes subjected to different kinds of stress (doxorubicin, ischemia/reperfusion) ADDIN REFMGR.CITE Kunisada1998574Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytesJournal574Activation of gp130 transduces hypertrophic signals via STAT3 in cardiac myocytesKunisada,K.Tone,E.Fujio,Y.Matsui,H.Yamauchi-Takihara,K.Kishimoto,T.1998/7/28AdenoviridaeAnimalsAntigens,CDAtrial Natriuretic FactorCardiomegalyCytokine Receptor gp130CytokinescytologyDNA-Binding ProteinsetiologyGenetic Vectorsgeneticsgp130Growth InhibitorshearthypertrophyInterleukin-6LeucineLeukemia Inhibitory FactorLymphokinesMembrane GlycoproteinsmetabolismmethodsMiceMutationMyocardiumNOpharmacologyPhosphorylationphysiologyphysiopathologyProto-Oncogene Proteins c-fosRNA,MessengerSignal TransductionSTAT1 Transcription FactorSTAT3 Transcription FactorTrans-ActivatorsTransfectionTyrosineNot in File346352Circulation.984Circulation.1Kunisada2000573Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathyJournal573Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathyKunisada,K.Negoro,S.Tone,E.Funamoto,M.Osugi,T.Yamada,S.Okabe,M.Kishimoto,T.Yamauchi-Takihara,K.2000/1/4ActinsAnimalsantagonists & inhibitorsAntineoplastic AgentsAtrial Natriuretic FactorCardiomegalyCardiomyopathieschemically inducedCytokinesDNA-Binding ProteinsDoxorubicinGene Expression Regulationgeneticsgp130heartheart failurehypertrophymetabolismMiceMice,TransgenicmortalityMyocardiumMyosin Heavy ChainsNOpathologypharmacologyRNA,MessengerSignal TransductionSTAT3 Transcription FactorsurvivalSurvival RateTrans-ActivatorsNot in File315319Proc.Natl.Acad.Sci.U.S.A.971Proc.Natl.Acad.Sci.U.S.A.1Negoro2001576Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutaseJournal576Activation of signal transducer and activator of transcription 3 protects cardiomyocytes from hypoxia/reoxygenation-induced oxidative stress through the upregulation of manganese superoxide dismutaseNegoro,S.Kunisada,K.Fujio,Y.Funamoto,M.Darville,M.I.Eizirik,D.L.Osugi,T.Izumi,M.Oshima,Y.Nakaoka,Y.Hirota,H.Kishimoto,T.Yamauchi-Takihara,K.2001/8/28AnimalsAnimals,NewbornCells,CulturedcytologyDNA-Binding Proteinsdrug effectsGene Expression Regulation,EnzymologicgeneticsGlutathioneGrowth InhibitorsInterleukin-6Leukemia Inhibitory FactorLymphokinesmetabolismmethodsMiceMyocardiumOxidative StressOxygenpharmacologyRatsRats,Sprague-Dawleyreactive oxygen speciesRecombinant Fusion ProteinsRNA,MessengerSTAT3 Transcription FactorStressSuperoxide DismutaseTrans-ActivatorsTransfectionUp-RegulationNot in File979981Circulation.1049Circulation.1189-191. Phosphorylation of STAT-3 at serine 727 by MAPKs and the PDGF receptor could provide an alternative pathway for activation ADDIN REFMGR.CITE Levy2002575What does Stat3 do?Journal575What does Stat3 do?Levy,D.E.Lee,C.K.2002/5Acute-Phase ProteinsAnimalscytologyDNA-Binding ProteinsEmbryoEpidermisEpithelial CellsmetabolismMyeloid Progenitor CellsNervous SystempathologyphysiologySTAT3 Transcription FactorT-LymphocytesThymus GlandTrans-ActivatorsNot in File11431148J.Clin.Invest.1099Journal of Clinical InvestigationJ.Clin.Invest.1192. STAT-3 affects capillary density and the composition of the extracellular matrix through maintaining a balance between anti-angiogenic (connective tissue growth factor, thrombospondin-1, tissue inhibitor of metalloproteinase 1) and pro-angiogenic factors (VEGF) ADDIN REFMGR.CITE Hilfiker-Kleiner2005572STAT3-mediated activation of myocardial capillary growthJournal572STAT3-mediated activation of myocardial capillary growthHilfiker-Kleiner,D.Limbourg,A.Drexler,H.2005/5AdultAnimalsCapillariesCardiac Output,LowCardiologyCoronary VesselsCytokinesdrug therapyembryologyEmbryonic DevelopmentEndothelial Cellsfibrosisgeneticsgrowth & developmentheartheart failureHomeostasisHumansmetabolismMicrocirculationNeovascularization,PathologicNeovascularization,PhysiologicOxygenPerfusionphysiologyphysiopathologyreviewSTAT3 Transcription FactorStresssurvivalVEGFNot in File152157Trends C a r d i o v a s c . M e d . < / P e r i o d i c a l > < V o l u m e > 1 5 < / V o l u m e > < I s s u e > 4 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > T r e n d s C a r d i o v a s c . M e d . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 8 8 .
T h e W n t p a t h w a y a n d - c a t e n i n
A r e c e n t l y d i s c overed pathway associated with cardiac hypertrophy is the Wnt/Frizzled (Fz) pathway (see HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e4.ppt"fig. e4). The putative sequence of signaling events is as follows: Wnt ligands (a large family of glycoproteins, secreted in a paracrine fashion) bind to a membrane-bound complex consisting of a member of the Fz receptor family and a LDL receptorrelated protein (LRP); activation of a member of the disheveled (Dvl) protein family follows; GSK-3 is subsequently inhibited; inhibition of GSK-3 as a result of Wnt signaling releases pro-hypertrophic transcription factors (e.g. GATA-4 and NFAT) and additionally contributes to hypertrophy by decreasing pho s p h o r y l a t i o n o f - c a t e n i n a n d a l l o w i n g i t t o a c c u m u l a t e i n t h e c y t o p l a s m A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > K i k u c h i < / A u t h o r > < Y e a r > 2 0 0 0 < / Y e a r > < R e c N u m > 6 8 5 < / R e c N u m > < I D T e x t > R e g u l a t i o n o f b e t a - c a t e n i n s i g n a l i n g i n t h e W n t p a t h w a y < / I D T e x t > < M D L R e f _ T y p e = " J ournal">Journal685Regulation of beta-catenin signaling in the Wnt pathwayKikuchi,A.2000/2/16Animalsbeta CateninCell AdhesionCell NucleusCytoplasmCytoskeletal ProteinsGenesHumansmetabolismProteinsProto-Oncogene ProteinsRepressor ProteinsSignal TransductionTrans-ActivatorsWnt ProteinsZebrafish ProteinsNot in File243248Biochem.Biophys.Res.Commun.2682Biochem.Biophys.Res.Commun. < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 9 3 . I t w a s r e c e n t l y q u e s t i o n e d w h e t h e r - c a t e n i n a c c u m u l a t i o n i s i n d e e d n e c e s s a r y f o r t h e h y p e r t r o p h i c r e s p o n s e . R a t h e r , i t w a s s u g g e s t e d t h a t a d a p a t i v e c a r d i a c r e m o d e l i n g a f t e r G P C R s t i m u l a t i o n r e q u i r e s - c a t e n i n d o w n r e g u l a t i o n A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > B a u r a n d < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 6 9 1 < / R e c N u m > < I D T e x t > B e t a - c a t e n i n d o w n r e g u l a t i o n i s r e q u i r e d f o r a d a p t i v e c a r d i a c r e m o d e l i n g < / I D T e x t > < M D L R e f _ T y p e = " J o u r n a l " > < R e f _ T y p e > J o urnal691Beta-catenin downregulation is required for adaptive cardiac remodelingBaurand,A.Zelarayan,L.Betney,R.Gehrke,C.Dunger,S.Noack,C.Busjahn,A.Huelsken,J.Taketo,M.M.Birchmeier,W.Dietz,R.Bergmann,M.W.2007/5/11AdultanalysisAngiotensin IIAnimalsantagonists & inhibitorsbeta CateninCardiomegalyCell MembraneetiologyGene Expression RegulationGenesgeneticsheartHomeostasishypertrophyInsulin-Like Growth Factor Binding Protein 5MiceMice,Inbred C57BLmodelpharmacologyphysiologyProteinsremodelingT-Box Domain ProteinsVentricular RemodelingNot in File13531362Circ.Res.1009Circ.Res.162 . - c a t e n i n i s a m a s t e r s w i t c h i n v o l v e d i n a m y r i a d o f c e l l f u n c t i o n s a n d i s c o - a c t i v a t e d b y m e m b e r s o f t h e T - c e l l f a c t o r / L y m p h o c y t e e n h a n c e r f a c t o r ( T c f / L e f ) f a m i l y o f t r a n s c r i p t i o n f a c t o r s . - c a t e n i n i s n o t o n l y o f i m p o r t a n c e t o t h e c a r d i a c h y p e r t r o p h i c response to pressure overload (together with Lef-1), but also to cell proliferation (e.g. cardiac progenitor cells) and survival under conditions of oxidative stress (by inducing cell cycle arrest and quiescence) ADDIN REFMGR.CITE Chen2006689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyJournal689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyChen,X.Shevtsov,S.P.Hsich,E.Cui,L.Haq,S.Aronovitz,M.Kerkela,R.Molkentin,J.D.Liao,R.Salomon,R.N.Patten,R.Force,T.2006/6Animalsbeta CateninCardiologyCardiomegalyCell CycleCell EnlargementCell ProliferationcytologydeficiencyetiologyGene DeletionGene Expressiongeneticsgrowth & developmentheartheart failurehypertrophyLymphoid Enhancer-Binding Factor 1metabolismMiceMice,Inbred C57BLMice,KnockoutMice,Mutant StrainsMice,TransgenicmodelMutationMyocytes,CardiacpathologyPhenotypeResearchSignal TransductionTCF Transcription FactorsTranscription FactorsNot in File44624473Mol.Cell Biol.2612Mol.Cell Biol.1Bowerman2005688Cell biology. Oxidative stress and cancer: a beta-catenin convergenceJournal688Cell biology. Oxidative stress and cancer: a beta-catenin convergenceBowerman,B.2005/5Animalsbeta CateninCaenorhabditis elegansCaenorhabditis elegans ProteinsCell CycleCell Line,TumorCell ProliferationCell SurvivalCytoskeletal ProteinsGene Expression RegulationgeneticsHumansLongevitymetabolismNeoplasmsOxidative StressphysiologyReceptor,InsulinSignal TransductionStressSuperoxide DismutasetherapyTrans-ActivatorsTranscription FactorsNot in File11191120Science.3085725Science.1Kwon2007738Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitorsJournal738Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitorsKwon,C.Arnold,J.Hsiao,E.C.Taketo,M.M.Conklin,B.R.Srivastava,D.2007/6/18beta CateninLigandsMesodermpharmacologyStem CellsNot in File1089410899Proc.Natl.Acad.Sci.U.S.A.10426Proc.Natl.Acad.Sci.U.S.A.147;194;195.
Interruption of Wnt signaling in mice lacking the Dvl-1 gene attenuated the onset of TAC-induced cardiac hypertrophy ADDIN REFMGR.CITE van de Schans2007686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyJournal686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyvan de Schans,V.van den Borne,S.W.Strzelecka,A.E.Janssen,B.J.van,der,VLangen,R.C.Wynshaw-Boris,A.Smits,J.F.Blankesteijn,W.M.2007/3Adaptor Proteins,Signal TransducinganalysisAnimalsAortic CoarctationAtrial Natriuretic Factorbeta CateninbiosynthesisCardiomegalycomplicationsConstrictionDisease Models,AnimaletiologyFemaleFrizzled ReceptorsGenesgeneticsGlycogen Synthase Kinase 3heartHypertensionhypertrophyMaleMiceMice,KnockoutNatriuretic PeptidespharmacologyPhosphoproteinsphysiologyphysiopathologyPressureProto-Oncogene Proteins c-aktResearchSignal TransductiontherapyultrasonographyWnt ProteinsNot in File473480Hypertension. 4 9 < / V o l u m e > < I s s u e > 3 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > H y p e r t e n s i o n . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 5 6 . I n t h e s e m i c e , t h e a m o u n t o f - c a t e n i n p r o t e i n w a s r e d u c e d a n d n a t r i u r e t i c p e p i d e u p r e g u l a tion was prevented. Unfortunately, no LV functional data were provided. It was suggested that Wnt inhibited GSK-3 directly and indirectly via activation of Akt1, the latter being of minor importance after 7 days of TAC (Akt1 presumably being upregulated in the first days of TAC only) ADDIN REFMGR.CITE van de Schans2007686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyJournal686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyvan de Schans,V.van den Borne,S.W.Strzelecka,A.E.Janssen,B.J.van,der,VLangen,R.C.Wynshaw-Boris,A.Smits,J.F.Blankesteijn,W.M.2007/3Adaptor Proteins,Signal TransducinganalysisAnimalsAortic CoarctationAtrial Natriuretic Factorbeta CateninbiosynthesisCardiomegalycomplicationsConstrictionDisease Models,AnimaletiologyFemaleFrizzled ReceptorsGenesgeneticsGlycogen Synthase Kinase 3heartHypertensionhypertrophyMaleMiceMice,KnockoutNatriuretic PeptidespharmacologyPhosphoproteinsphysiologyphysiopathologyPressureProto-Oncogene Proteins c-aktResearchSignal TransductiontherapyultrasonographyWnt ProteinsNot in File473480Hypertension.493 H y p e r t e n s i o n . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 5 6 . S i m i l a r l y , c a r d i a c s p e c i f i c d i s r u p t i o n o f - c a t e n i n / L e f - 1 s i g n a l i n g p r e v e n t e d T A C - i n d u c e d m y o c a r d i a l h y p e r t r o p h y A D D I N R E F M G R . C I T E < R e f m a n > < C i t e >Chen2006689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyJournal689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyChen,X.Shevtsov,S.P.Hsich,E.Cui,L.Haq,S.Aronovitz,M.Kerkela,R.Molkentin,J.D.Liao,R.Salomon,R.N.Patten,R.Force,T.2006/6Animalsbeta CateninCardiologyCardiomegalyCell CycleCell EnlargementCell ProliferationcytologydeficiencyetiologyGene DeletionGene Expressiongeneticsgrowth & developmentheartheart failurehypertrophyLymphoid Enhancer-Binding Factor 1metabolismMiceMice,Inbred C57BLMice,KnockoutMice,Mutant StrainsMice,TransgenicmodelMutationMyocytes,CardiacpathologyPhenotypeResearchSignal TransductionTCF Transcription FactorsTranscription FactorsNot in File44624473Mol.Cell Biol.2612Mol.Cell Biol.147 . - c a t e n i n i s a k e y c o m p o n e n t o f a d h e r e n s j u n c t i o n s , w h i c h a r e s t r u c t u r e s t h a t h o l d e p i t h e l i a l c e l l s t o g e t h e r , a s w e l l a s c a r d i o m y o c y t e s i n t h e i n t e r c a l a t e d d i s c A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > B o w e r m a n < / A u t h o r > < Y e a r > 2 0 0 5 < / Y e a r > < R e c N u m > 6 8 8 < / R e c N um>Cell biology. Oxidative stress and cancer: a beta-catenin convergenceJournal688Cell biology. Oxidative stress and cancer: a beta-catenin convergenceBowerman,B.2005/5Animalsbeta CateninCaenorhabditis elegansCaenorhabditis elegans ProteinsCell CycleCell Line,TumorCell ProliferationCell SurvivalCytoskeletal ProteinsGene Expression RegulationgeneticsHumansLongevitymetabolismNeoplasmsOxidative StressphysiologyReceptor,InsulinSignal TransductionStressSuperoxide DismutasetherapyTrans-ActivatorsTranscription FactorsNot in File11191120Science.3085725Science.1Schroen2007690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophyJournal690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophySchroen,B.Leenders,J.J.van,Erk A.Bertrand,A.T.van,Loon M.van Leeuwen,R.E.Kubben,N.Duisters,R.F.Schellings,M.W.Janssen,B.J.Debets,J.J.Schwake,M.Hoydal,M.A.Heymans,S.Saftig,P.Pinto,Y.M.2007/5/21hypertrophyNot in Filei5J Cell Biol.1774J Cell Biol.157;194 . T h e l a t t e r f a c t c o u l d b e e s s e n t i a l f o r - c a t e n i n s r o l e i n m y o c a r d i a l h y p e r t r o p h y , s i n c e i t h a s b e e n s h o w n t h a t i n t e r r u p t i o n o f t h e b i n d i n g o f - c a t e n i n t o c a d h e r i n i n t h e i n t e r c a l a t e d d i s c ( b y t r a n s g e n i c l o s s o f l y s o s o m a l i n t e g r a l m e m b r a n e p r o t e i n 2 ( L I M P - 2 ) e x p r e s s i o n ) , p r e v e n t s T A C - i n d u c e d h y p e r t r o p h y a n d l e a d s t o h e a r t f a i l u r e A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > S c h r o e n < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 6 9 0 < / R e c N u m > < I D T e x t > L y s o s o m a l i n t e g r a l m e m b r a n e p r o t e i n 2 i s a n o v e l c o m p o n e n t o f t h e c a r d i a c intercalated disc and vital for load-induced cardiac myocyte hypertrophyJournal690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophySchroen,B.Leenders,J.J.van,Erk A.Bertrand,A.T.van,Loon M.van Leeuwen,R.E.Kubben,N.Duisters,R.F.Schellings,M.W.Janssen,B.J.Debets,J.J.Schwake,M.Hoydal,M.A.Heymans,S.Saftig,P.Pinto,Y.M.2007/5/21hypertrophyNot in Filei5J Cell Biol.1774J Cell Biol.157. In contrast with these findings, another study showed that ATII-induced cardiac hypertrophy was prevented by transgenic cardiac s p e c i f i c s t a b i l i z a t i o n o f - c a t e n i n , w h i c h w a s a c c o m p a n i e d b y a d e c r e a s e d s y s t o l i c f u n c t i o n a n d u n r e l a t e d t o a p o p t o s i s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > B a u r a n d < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 6 9 1 < / R e c N u m > < I D T e x t > B e t a - c a t e n i n d o w n r e g u l a t i o n i s r e quired for adaptive cardiac remodelingJournal691Beta-catenin downregulation is required for adaptive cardiac remodelingBaurand,A.Zelarayan,L.Betney,R.Gehrke,C.Dunger,S.Noack,C.Busjahn,A.Huelsken,J.Taketo,M.M.Birchmeier,W.Dietz,R.Bergmann,M.W.2007/5/11AdultanalysisAngiotensin IIAnimalsantagonists & inhibitorsbeta CateninCardiomegalyCell MembraneetiologyGene Expression RegulationGenesgeneticsheartHomeostasishypertrophyInsulin-Like Growth Factor Binding Protein 5MiceMice,Inbred C57BLmodelpharmacologyphysiologyProteinsremodelingT-Box Domain ProteinsVentricular RemodelingNot in File13531362Circ.Res.1009Circ.Res.162 . I n t h i s s t u d y , c a r d i a c s p e c i f i c d e p l e t i o n o f - c a t e n i n r e s u l t e d i n m i l d c a r d i a c h y p e r t r o p h y u n d e r b a s e l i n e c o n d i t i o n s a n d e n h a n c e d t h e h y p e r t r o p h i c r e s p o n s e t o A T I I A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > B a u r a n d < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 6 9 1 < / R ecNum>Beta-catenin downregulation is required for adaptive cardiac remodelingJournal691Beta-catenin downregulation is required for adaptive cardiac remodelingBaurand,A.Zelarayan,L.Betney,R.Gehrke,C.Dunger,S.Noack,C.Busjahn,A.Huelsken,J.Taketo,M.M.Birchmeier,W.Dietz,R.Bergmann,M.W.2007/5/11AdultanalysisAngiotensin IIAnimalsantagonists & inhibitorsbeta CateninCardiomegalyCell MembraneetiologyGene Expression RegulationGenesgeneticsheartHomeostasishypertrophyInsulin-Like Growth Factor Binding Protein 5MiceMice,Inbred C57BLmodelpharmacologyphysiologyProteinsremodelingT-Box Domain ProteinsVentricular RemodelingNot in File13531362Circ.Res.1009Circ.Res.162. These divergent responses may have resulted from differences i n s t i m u l i ( T A C v s A T I I ) , d i f f e r e n c e s i n t r a n s g e n i c a p p r o a c h e s a n d d i f f e r e n t i n t e r v a l s b e t w e e n g e n e t i c t a r g e t i n g o f t h e W n t p a t h w a y a n d s u b s e q u e n t i n d u c t i o n o f h y p e r t r o p h y . C a n c e r r e s e a r c h h a s s h o w n t h a t H I F - 1 a n d - c a t e n i n i n t e r a c t i n t h e c e l l u l a r r e s p o n s e t o h y p o x i a ( s e e b e l o w ) A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > K a i d i < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 7 3 7 < / R e c N u m > < I D T e x t > I n t e r a c t i o n b e t w e e n b e t a - c a t e n i n a n d H I F - 1 p r o m o t e s c e l l u l a r a d a p t a t i o n t o h y p o x i a < / I D T e x t > < M D L R e f _ T y p e = " J o u r n a l " > < R e f _ T y p e > J o u r n al737Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxiaKaidi,A.Williams,A.C.Paraskeva,C.2007/2Adaptation,PhysiologicalAnoxiabeta CateninCell Line,TumorCell ProliferationCell SurvivalCell Transformation,NeoplasticColonic NeoplasmsGenesHIF-1alphaHumanshypoxiaHypoxia-Inducible Factor 1metabolismResearchSignal TransductionsurvivalNot in File210217Nat.Cell Biol.92Nat.Cell Biol.1196.
The female factor
One of the intriguing aspects of PAH epidemiology is the gender difference in prevalence. Over the human life span, there are two female incidence peaks: one in early adulthood and one after the menopause ADDIN REFMGR.CITE Humbert2006213Pulmonary Arterial Hypertension in France: Results from a National RegistryJournal213Pulmonary Arterial Hypertension in France: Results from a National RegistryHumbert,MarcSitbon,OlivierChaouat,AriBertocchi,MicheleHabib,GilbertGressin,VirginieYaici,AzzedineWeitzenblum,EmmanuelCordier,Jean FrancoisChabot,FrancoisDromer,ClairePison,ChristopheReynaud-Gaubert,MartineHaloun,AlainLaurent,MarcelHachulla,EricSimonneau,Gerald2006/5/1pulmonary hypertensionregistryNot in File10231030Am.J.Respir.Crit.Care Med.1739http://ajrccm.atsjournals.org/cgi/content/abstract/173/9/1023http://ajrccm.atsjournals.org/cgi/reprint/173/9/1023American Journal of Respiratory and Critical Care MedicineAm.J.Respir.Crit.Care Med.1197. While the first peak could be related to the use of anorexigens, a known risk factor for PAH, the second peak is also present in connective tissue diseases and could be due to female sex hormone deficiency. Ovariectomized rats exposed to chronic hypoxia or MCT develop more severe pulmonary hypertension than animals with intact ovaries ADDIN REFMGR.CITE Farhat1993543Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in ratsJournal543Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in ratsFarhat,M.Y.Chen,M.F.Bhatti,T.Iqbal,A.Cathapermal,S.Ramwell,P.W.1993/10AnimalsBehavior,AnimalBody Weightchemically induceddrug effectsDrug ImplantsEstradiolHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyHypertrophy,Right VentricularLungMacrophagesMalemonocrotalineMyocardiumNOOrgan SizepathologypharmacologyphysiologyphysiopathologyPulmonary ArteryPulmonary Circulationpulmonary edemapulmonary hypertensionRatsRats,Sprague-Dawleyright ventricleNot in File719723Br.J.Pharmacol.1102Br.J.Pharmacol.1Rabinovitch1981544Age and sex influence on pulmonary hypertension of chronic hypoxia and on recoveryJournal544Age and sex influence on pulmonary hypertension of chronic hypoxia and on recoveryRabinovitch,M.Gamble,W.J.Miettinen,O.S.Reid,L.1981/1AdultAge FactorsAnimalsAnoxiabloodBlood PressureCardiomegalyChronic DiseaseFemaleHemodynamic ProcessesHypertensionHypertension,PulmonaryhypoxiaMalemuscleMuscle,Smooth,VascularOxygenphysiopathologyPulmonary ArteryPulmonary Circulationpulmonary hypertensionRatsSex FactorsNot in FileH62H72Am.J.Physiol.2401Am.J.Physiol.11;6. Obviously, by limiting the progression of pulmonary vascular remodeling in these models, estrogens delayed right heart failure. However, there are also a number of direct effects of estrogens on the heart that could be cardio-protective. Most cardiovascular research has focused on the potential of 2-methoxyestradiol (2-ME) as a possible drug. Among possible protective effects of 2-ME are inhibition of ET-1 synthesis, reduction of mast cell related MMP activation and stimulation of PGI2 synthesis ADDIN REFMGR.CITE Dubey2001545Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanismJournal545Estradiol metabolites inhibit endothelin synthesis by an estrogen receptor-independent mechanismDubey,R.K.Jackson,E.K.Keller,P.J.Imthurn,B.Rosselli,M.2001/2analogs & derivativesAnimalsantagonists & inhibitorsbiosynthesisCells,CulturedCoronary VesselsdeficiencyDose-Response Relationship,Drugdrug effectsendothelin-1EndothelinsEstradiolEstrogen Receptor betaFemalemetabolismMiceMitogen-Activated Protein KinasesmuscleMuscle,Smooth,VascularpharmacologyReceptors,EstrogenSwineTime FactorsNot in File640644Hypertension.372 Part 2Hypertension.1Chancey2005506Modulation of cardiac mast cell-mediated extracellular matrix degradation by estrogenJournal506Modulation of cardiac mast cell-mediated extracellular matrix degradation by estrogenChancey,A.L.Gardner,J.D.Murray,D.B.Brower,G.L.Janicki,J.S.2005/7AnimalsBlood PressureBlood VolumeCell Degranulationchemically inducedCollagencytologyDiastolediastolic functiondrug effectsenzymologyEstradiolExtracellular MatrixFemaleheartheart failureMaleMast CellsMatrix Metalloproteinase 2metabolismmodelMyocardiumNOOvariectomyp-Methoxy-N-methylphenethylaminepharmacologyphysiologyRatsRats,Sprague-DawleyremodelingVentricular Function,LeftVentricular RemodelingNot in FileH316H321Am.J.Physiol Heart Circ.Physiol.2891Am.J.Physiol Heart Circ.Physiol.1Seeger1999546Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell culturesJournal546Effect of estradiol metabolites on prostacyclin synthesis in human endothelial cell culturesSeeger,H.Mueck,A.O.Lippert,T.H.1999analogs & derivativesbiosynthesisCells,CulturedEndothelium,VascularepoprostenolEstradiolEstroneHumansHydroxyestronesmetabolismpharmacologyprostacyclinNot in FileL167L170Life Sci.6513 < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > L i f e S c i . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 9 8 - 2 0 0 . I n c o n t r a s t , s o m e M E - 2 r e l a t e d m e c h a n i s m s t h a t h a v e b e e n d e m o n s t r a t e d i n c a n c e r t i s s u e c o u l d c o n t r i b u t e t o t h e d e v e l o p m e n t o f r i g h t h e a r t f a i l u r e : p o s t - t r a n s c r i p t i o n a l i n h i b i t i o n o f H I F - 1 , g e n e r a t i o n o f R O S a n d a c t i v a t i o n o f p r o - a p o p t o t i c p a t h w a y s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > M a b j e e s h < / A u t h o r > < Y e a r > 2 0 0 3 < / Y e a r > < R e c N u m > 5 4 8 < / R e c N u m > < I D T e x t > 2 M E 2 i n h i b i t s t umor growth and angiogenesis by disrupting microtubules and dysregulating HIFJournal5482ME2 inhibits tumor growth and angiogenesis by disrupting microtubules and dysregulating HIFMabjeesh,N.J.Escuin,D.LaVallee,T.M.Pribluda,V.S.Swartz,G.M.Johnson,M.S.Willard,M.T.Zhong,H.Simons,J.W.Giannakakou,P.2003/4analogs & derivativesAnimalsblood supplyBlotting,NorthernBreast NeoplasmsclinicalClinical TrialsCytoskeletonDNA-Binding Proteinsdrug effectsdrug therapyEndothelial Growth FactorsEstradiolGene Expression Regulation,NeoplasticgeneticsHumansHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1,alpha SubunitImmunohistochemistryIntercellular Signaling Peptides and ProteinsLymphokinesmetabolismMiceMicroscopy,ConfocalMicrotubulesModels,AnimalNeovascularization,PathologicNuclear ProteinspathologypharmacologyRNA,MessengerTranscription FactorsTranscription,GeneticTumor Cells,CulturedVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVEGFNot in File363375Cancer Cell.34Cancer Cell.1Mooberry2003549New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agentJournal549New insights into 2-methoxyestradiol, a promising antiangiogenic and antitumor agentMooberry,S.L.2003/11analogs & derivativesAngiogenesis InhibitorsAnimalsapoptosisBone Marrow NeoplasmsclinicalClinical Trialsdrug therapyEstradiolHumansHypoxia-Inducible Factor 1modelMultiple MyelomaNeovascularization,PathologicOxygenpharmacologyphysiologyreactive oxygen speciesResearchreviewSignal Transductiontherapeutic useNot in File425430Curr.Opin.Oncol.156Curr.Opin.Oncol.1201;202. 2-ME activates different MAPK pathways (ERK1/2, p38 and JNK) in the lung ADDIN REFMGR.CITE Bogatcheva2007547Involvement of microtubules, p38, and Rho kinases pathway in 2-methoxyestradiol-induced lung vascular barrier dysfunctionJournal547Involvement of microtubules, p38, and Rho kinases pathway in 2-methoxyestradiol-induced lung vascular barrier dysfunctionBogatcheva,N.V.Adyshev,D.Mambetsariev,B.Moldobaeva,N.Verin,A.D.2007/2ActomyosinAmidesanalogs & derivativesBlood-Air BarrierCell Membrane Permeabilityclinicalcytologydeficiencydrug effectsEndothelial CellsendotheliumenzymologyEstradiolHumansImidazolesIntracellular Signaling Peptides and ProteinsLungmetabolismMicroelectrodesMicrotubulesModels,BiologicalMyosin-Light-Chain Kinasep38 Mitogen-Activated Protein KinasesPaclitaxelpharmacologyPhosphorylationphysiopathologyProtein-Serine-Threonine KinasesPulmonary ArteryPyridinesRhoRnaStressTubulinNot in FileL487L499Am.J.Physiol Lung Cell Mol.Physiol.2922Am.J.Physiol Lung Cell Mol.Physiol.1203, if the same would hold true in the heart the end result would be hard to predict. Many effects of 2-ME are independent from estrogen receptor binding, which may explain why other estrogens exert different effects. H i g h d o s e 1 7 e s t r a d i o l h a s b e e n r e c e n t l y s h o w n t o p r e v e n t t h e t r a n s i t i o n f r o m h y p e r t r o p h y t o f a i l u r e i n a g e n e t i c m o d e l f o r s p o n t a n e o u s h e a r t f a i l u r e , w h i c h w a s a s s o c i a t e d w i t h a n t i o x i d a n t m e c h a n i s m s ( i n h i b i t i o n o f N A D P H o x i d a s e a n d u p r e g u l a t i o n o f t h i o r e d oxin, Trx) and reduced apoptosis (inhibition of apoptosis signal-regulating kinase 1(ASK-1) and its downstream MAPKs p38 and JNK) ADDIN REFMGR.CITE Satoh2007736Inhibition of Apoptosis-Regulated Signaling Kinase-1 and Prevention of Congestive Heart Failure by EstrogenJournal736Inhibition of Apoptosis-Regulated Signaling Kinase-1 and Prevention of Congestive Heart Failure by EstrogenSatoh,M.Matter,C.M.Ogita,H.Takeshita,K.Wang,C.Y.Dorn,G.W.Liao,J.K.2007/6/11AdenineapoptosisCardiologycontractilityheartheart failurehypertrophyIncidenceMalemethodsMicephysiologyResearchtherapyNot in File31973204Circulation.11525Circulation.1204.
Control of gene expression by histone acetylation/deacetylation
A central mechanism for gene regulation in eukaryotes is histone-dependent packaging of genomic DNA. When there is no transcription, DNA is wrapped around histone octameres in nucleosomes, which are the basic units of chromatin. The highly compact structure that is formed by interacting nucleosomes limits access of transcriptional enzymes to genomic DNA, thereby repressing gene expression ADDIN REFMGR.CITE Fischle2003449Histone and chromatin cross-talkJournal449Histone and chromatin cross-talkFischle,W.Wang,Y.Allis,C.D.2003/4AnimalsCell NucleusChromatinDnaEukaryotic CellsGene Expression RegulationgeneticsGenomeHistonesHumansmetabolismProtein Processing,Post-TranslationalreviewSignal TransductionNot in File172183Curr.Opin.Cell Biol.152Curr.Opin.Cell Biol.1205. Acetylation of histones by HATs (e.g. p300, when co-activated by CREB) relaxes the nucleosomal structures, thereby facilitating gene expression. The opposite effect is established by class II HDACs, which repress transcription and constitutively inhibit hypertrophic pathways ADDIN REFMGR.CITE Backs2006694Control of cardiac growth by histone acetylation/deacetylationJournal694Control of cardiac growth by histone acetylation/deacetylationBacks,J.Olson,E.N.2006/1/6AcetylationAnimalsCardiomegalyChromatinDnaetiologyGene Expressiongrowth & developmentheartheart failureHistone AcetyltransferasesHistone DeacetylasesHistonesHumansMADS Domain ProteinsmetabolismMyogenic Regulatory FactorsphysiologyProtein Kinase CProtein Processing,Post-TranslationalremodelingSignal TransductionStressTranscription FactorsTranscription,GeneticNot in File1524Circ.Res.981Circ.Res.1125. One strategy to override HDAC activity is by exporting it out of the nucleus (nucleocytoplasmic shuttling). The latter mechanism has been shown to be involved in the regulation of the activity of the MEF2 transcription factor in cardiac hypertrophy ADDIN REFMGR.CITE McKinsey2000617Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiationJournal617Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiationMcKinsey,T.A.Zhang,C.L.Lu,J.Olson,E.N.2000/11/2AnimalsBasic Helix-Loop-Helix Transcription FactorsCa(2+)-Calmodulin Dependent Protein KinaseCell DifferentiationCell LineCell NucleusCos CellscytologyDNA-Binding ProteinsgeneticsHistone DeacetylasesHistonesmetabolismmuscleMuscle,SkeletalMutagenesisMyogenic Regulatory FactorsPhosphorylationProtein TransportProteinsRepressor ProteinsSignal TransductionTranscription FactorsNot in File106111Nature.4086808Nature.1Youn2000450Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4Journal450Calcium regulates transcriptional repression of myocyte enhancer factor 2 by histone deacetylase 4Youn,H.D.Grozinger,C.M.Liu,J.O.2000/7/21Amino Acid SequenceapoptosiscalciumCalmodulinchemistryDNA-Binding ProteinsGene Expression RegulationgeneticsHistone DeacetylasesHumansJurkat CellsmetabolismMolecular Sequence DatamuscleMyogenic Regulatory FactorsSignal TransductionsurvivalTranscription FactorsTranscription,GeneticNot in File2256322567J.Biol.Chem.27529Journal of Biological ChemistryJ.Biol.Chem.185;206. Nucleocytoplasmic transfer of HDACs can be established by PKC signaling (with activation of PKD as an intermediate step), and this could be one of the ways that GPCR agonists use to induce transcription of hypertrophic factors ADDIN REFMGR.CITE Harrison2006451Regulation of cardiac stress signaling by protein kinase d1Journal451Regulation of cardiac stress signaling by protein kinase d1Harrison,B.C.Kim,M.S.van,Rooij E.Plato,C.F.Papst,P.J.Vega,R.B.McAnally,J.A.Richardson,J.A.Bassel-Duby,R.Olson,E.N.McKinsey,T.A.2006/5AnimalsAnimals,NewbornCardiomyopathiesCardiomyopathy,HypertrophicCatalytic DomainCells,CulturedCercopithecus aethiopsCos CellscytologyEnzyme ActivationfibrosisGene Expression RegulationgeneticsGPCRheartHeart VentriclesHypertensionhypertrophyIsoenzymesMalemetabolismMiceMice,TransgenicmodelModels,BiologicalmuscleMyocardial InfarctionMyocytes,CardiacpathologyPhosphorylationphysiologyProtein Kinase CProtein KinasesRatsRats,Inbred SHRRats,Inbred WFRats,Sprague-DawleyremodelingRhoRnaRNA,Small InterferingSignal TransductionStressNot in File38753888Mol.Cell Biol.2610Mol.Cell Biol.1207. Surprisingly, HDAC in h i b i t o r s d o n o t i n c r e a s e h y p e r t r o p h y b u t s t r o n g l y s u p p r e s s a g o n i s t - d e p e n d e n t c a r d i a c h y p e r t r o p h y a n d i n c r e a s e - M H C l e v e l s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > A n t o s < / A u t h o r > < Y e a r > 2 0 0 3 < / Y e a r > < R e c N u m > 4 5 4 < / R e c N u m > < I D T e x t > D o s e - d e p e n d e n t b l o c k a d e t o c a r d i omyocyte hypertrophy by histone deacetylase inhibitorsJournal454Dose-dependent blockade to cardiomyocyte hypertrophy by histone deacetylase inhibitorsAntos,C.L.McKinsey,T.A.Dreitz,M.Hollingsworth,L.M.Zhang,C.L.Schreiber,K.Rindt,H.Gorczynski,R.J.Olson,E.N.2003/8/1Adenylate Kinaseadministration & dosageanalysisAnimalsAnimals,Newbornantagonists & inhibitorsAtrial Natriuretic FactorCardiomegalyCells,CulturedchemistryclinicalClinical TrialsDnaDose-Response Relationship,Drugdrug effectsEnzyme InhibitorsFetusFluorescent Antibody Technique,IndirectGene Expressiongeneticsheartheart failureHistone DeacetylaseshypertrophyLeucinemetabolismMiceMyocardiumpathologyphysiologyprevention & controlRatsRats,Sprague-DawleyStressTritiumVentricular MyosinsNot in File2893028937J.Biol.Chem.27831Journal of Biological ChemistryJ.Biol.Chem.1208. Recent findings may explain this paradox, since it was demonstrated that class I HDACs (e.g. Hdac2) constitutively repress anti-hypertrophic pathways such as GSK-3 ADDIN REFMGR.CITE Trivedi2007606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityJournal606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityTrivedi,C.M.Luo,Y.Yin,Z.Zhang,M.Zhu,W.Wang,T.Floss,T.Goettlicher,M.Noppinger,P.R.Wurst,W.Ferrari,V.A.Abrams,C.S.Gruber,P.J.Epstein,J.A.2007/3AdultAnimalsbiosynthesisCardiomegalydeficiencyembryologyEnzyme ActivationenzymologyFetusgeneticsGlycogen Synthase Kinase 3heartheart failureHistone DeacetylaseshypertrophyIsoenzymesmetabolismMiceMice,KnockoutMice,TransgenicMolecular Sequence DataphysiologyRepressor ProteinsResearchSignal TransductionStressNot in File324331Nat.Med.133Nat.Med.151.
Translational repression by microRNAs (miRNAs)
miRNAs are small RNA molecules that negatively modulate gene expression through base paring to mRNAs, thereby inducing their cleavage and/or translational repression. miRNAs are involved in a variety of biological processes, including apoptosis, cell proliferation, tumor suppression and stress responses ADDIN REFMGR.CITE Bartel2004633MicroRNAs: genomics, biogenesis, mechanism, and functionJournal633MicroRNAs: genomics, biogenesis, mechanism, and functionBartel,D.P.2004/1/23AnimalsBase SequenceCaenorhabditis elegansDrosophilaGenomeHumansmetabolismMicroRNAsModels,BiologicalMolecular Sequence DataPhenotypephysiologyPlant ProteinsProtein BiosynthesisResearchRnaRNA,Small InterferingSpecies SpecificityTranscription,GeneticNot in File281297Cell.1162Cell.1209. In human heart failure, there seems to be reactivation of a fetal microRNA program that may contribute to alterations of gene expression ADDIN REFMGR.CITE Thum2007744MicroRNAs in the Human Heart. A Clue to Fetal Gene Reprogramming in Heart FailureJournal744MicroRNAs in the Human Heart. A Clue to Fetal Gene Reprogramming in Heart FailureThum,ThomasGaluppo,PaoloWolf,ChristianFiedler,JanKneitz,Susannevan Laake,Linda W.Doevendans,Pieter A.Mummery,Christine L.Borlak,JurgenHaverich,AxelGross,CarinaEngelhardt,StefanErtl,GeorgBauersachs,Johann2007/7/2Gene Expressionheartheart failurehypertrophyMicroRNAsNot in File258267Circulation1163http://circ.ahajournals.org/cgi/content/abstract/CIRCULATIONAHA.107.687947v1Circulation1210. miRNA-133 has been recently shown to control cardiac hypertrophy in mice ADDIN REFMGR.CITE Care2007634MicroRNA-133 controls cardiac hypertrophyJournal634MicroRNA-133 controls cardiac hypertrophyCare,A.Catalucci,D.Felicetti,F.Bonci,D.Addario,A.Gallo,P.Bang,M.L.Segnalini,P.Gu,Y.Dalton,N.D.Elia,L.Latronico,M.V.Hoydal,M.Autore,C.Russo,M.A.Dorn,G.W.Ellingsen,O.Ruiz-Lozano,P.Peterson,K.L.Croce,C.M.Peschle,C.Condorelli,G.2007/5hearthypertrophyMicroRNAsmodeloncologySignal TransductionNot in File613618Nat.Med.135Nat.Med.152. Exercise, TAC and selective cardiac overexpression of Akt1 were associated with reduced expression of miRNA-133 and suppression of miRNA-133 by decoy sequences induced hypertrophy in the absence of a stimulus. Some pro-hypertrophic target proteins normally inhibited by miRNA-133 were identified: RhoA, Cdc42 and Nelf-A/WHSC2. Moreover, in dilated atria of humans with mitral stenosis a 50% reduction in miRNA-133 expression was observed ADDIN REFMGR.CITE Care2007634MicroRNA-133 controls cardiac hypertrophyJournal634MicroRNA-133 controls cardiac hypertrophyCare,A.Catalucci,D.Felicetti,F.Bonci,D.Addario,A.Gallo,P.Bang,M.L.Segnalini,P.Gu,Y.Dalton,N.D.Elia,L.Latronico,M.V.Hoydal,M.Autore,C.Russo,M.A.Dorn,G.W.Ellingsen,O.Ruiz-Lozano,P.Peterson,K.L.Croce,C.M.Peschle,C.Condorelli,G.2007/5hearthypertrophyMicroRNAsmodeloncologySignal TransductionNot in File613618Nat.Med.135Nat.Med.152. In another study, miRNA-208 has been shown to mediate myocardia l f i b r o s i s a n d t h e s w i t c h f r o m M H C t o M H C i n r e s p o n s e t o T A C A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > V a n R o o i j E . < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 6 3 5 < / R e c N u m > < I D T e x t > C o n t r o l o f s t r e s s - d e p e n d e n t c a r d i a c g r o w t h a n d g e n e e x p r e s s i o n b y a m i c r o R N A < / I D T e x t >Journal635Control of stress-dependent cardiac growth and gene expression by a microRNAVan Rooij E.Sutherland,L.B.Qi,X.Richardson,J.A.Hill,J.Olson,E.N.2007/4/27AnimalsCardiac MyosinsCardiomegalycontractilityDown-RegulationfibrosisGene DeletionGene ExpressionGene Expression RegulationgeneticsheartHeart DiseaseshypertrophyHypothyroidismIntronsmetabolismMiceMice,TransgenicMicroRNAsMyocardial ContractionMyocardiumMyocytes,CardiacMyosin Heavy ChainsOligonucleotide Array Sequence AnalysispathologyphysiologyphysiopathologyProteinsRatsSignal TransductionStressTranscription FactorsTriiodothyronineUp-RegulationVentricular MyosinsNot in File575579Science.3165824Science.153.
4. Reactive oxygen species and reactive nitrogen species in heart failuire
Excessive production of ROS in heart failure can result from upregulation of xanthine oxidase (XO), NAD(P)H oxidases, cytochrome P450 and auto-oxidation of catecholamines ADDIN REFMGR.CITE Giordano2005428Oxygen, oxidative stress, hypoxia, and heart failureJournal428Oxygen, oxidative stress, hypoxia, and heart failureGiordano,F.J.2005/3AnimalsAnoxiacalciumCardiac Output,LowcytologyEnergy MetabolismGene ExpressionGene Expression Regulationheartheart failureHumanshypertrophyhypoxiaIon ChannelsLipidsmetabolismmitochondriaMyocardial IschemiaMyocardiumOxidative StressOxygenpathologyphysiologyphysiopathologyreactive oxygen speciesSignal TransductiontoxicityNot in File500508J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1Cappola2001435Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathyJournal435Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathyCappola,T.P.Kass,D.A.Nelson,G.S.Berger,R.D.Rosas,G.O.Kobeissi,Z.A.Marban,E.Hare,J.M.2001/11/13Allopurinolantagonists & inhibitorsCardiologyCardiomyopathiesCardiomyopathy,Dilateddrug effectsdrug therapyEnergy MetabolismEnzyme InhibitorsFemaleheartheart failureHemodynamic ProcessesHumansMalemetabolismmethodsMiddle AgedmodelMyocardial ContractionMyocardiumNOOxidative StressOxygenOxygen ConsumptionpharmacologyphysiopathologytherapyVentricular Dysfunction,LeftVentricular PressureXanthine OxidaseNot in File24072411Circulation.10420Circulation.1Heymes2003439Increased myocardial NADPH oxidase activity in human heart failureJournal439Increased myocardial NADPH oxidase activity in human heart failureHeymes,C.Bendall,J.K.Ratajczak,P.Cave,A.C.Samuel,J.L.Hasenfuss,G.Shah,A.M.2003/6/18AdultanalysisCardiologyChemiluminescent MeasurementsenzymologyGene Expressiongeneticsheartheart failureHeart Failure,CongestiveHumansHypertensionmethodsMiddle AgedmodelMyocardiumNadpOxidative StressOxygenpathologyphysiologyreactive oxygen speciesReverse Transcriptase Polymerase Chain ReactionNot in File21642171J.Am.Coll.Cardiol.4112J.Am.Coll.Cardiol.1212;226;227. Constitutively expressed endothelial NO synthase (eNOS or NOS3) and hemoglobin are the principal sources of reactive nitrogen species (RNS) in the heart, including NO and SNOs (NO-modified cysteine thiols in amino acids, peptides, and proteins). Sustained desaturation of hemoglobin contributes to a NO/redox disequilibrium ADDIN REFMGR.CITE Hare2005438NO/redox disequilibrium in the failing heart and cardiovascular systemJournal438NO/redox disequilibrium in the failing heart and cardiovascular systemHare,J.M.Stamler,J.S.2005/3adverse effectsAnimalsbloodCardiac Output,LowCardiologyCardiovascular AgentsCardiovascular Systemcytologydrug therapyheartHomeostasisHumansmetabolismMyocardiumnitric oxideOxidation-ReductionOxygenpathologyPhenotypephysiologyphysiopathologyReactive Nitrogen Speciesreactive oxygen speciesSignal Transductiontherapeutic useNot in File509517J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1149. The resulting decreased levels of S-nitrosylated hemoglobin (SNO-Hb) impair red blood cell induced vasodilatation and contribute to reduced tissue perfusion in heart failure ADDIN REFMGR.CITE Datta2004441Red blood cell nitric oxide as an endocrine vasoregulator: a potential role in congestive heart failureJournal441Red blood cell nitric oxide as an endocrine vasoregulator: a potential role in congestive heart failureDatta,B.Tufnell-Barrett,T.Bleasdale,R.A.Jones,C.J.Beeton,I.Paul,V.Frenneaux,M.James,P.2004/3/23Allosteric RegulationanalysisAnimalsAnoxiaAorta,Thoracicbloodcardiac outputCardiologyCell HypoxiaErythrocytesFemaleheartheart failureHeart Failure,CongestivehemoglobinHemoglobinsHumanshypoxiaIronLungMalemetabolismmethodsMiddle Agednitric oxideNitrogen OxidesnitrosylhemoglobinNOOxygenoxygen extractionPartial PressurepharmacologyphysiologyRabbitsS-NitrosoglutathioneVasodilationNot in File13391342Circulation.10911Circulation.1228, with subsequent RAS activation. Uncoupling of NOS3 further contributes to ROS generation ADDIN REFMGR.CITE Kuzkaya2003527Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthaseJournal527Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthaseKuzkaya,N.Weissmann,N.Harrison,D.G.Dikalov,S.2003/6analogs & derivativesAnimalsAortaAscorbic AcidBiopterinCardiologyCattleCells,CulturedchemistrydeficiencyEndothelium,VasculareNOSenzymologyKineticsmetabolismnitric oxideNitric Oxide DonorsNitric Oxide SynthaseNitric Oxide Synthase Type IIIPeroxynitrous AcidpharmacologySpin LabelsSulfhydryl CompoundsNot in File2254622554J.Biol.Chem.27825Journal of Biological ChemistryJ.Biol.Chem.1229. NOS3 is normally present as a homodimer, but chronic pressure overload is associated with uncoupling of NOS3 and monomeric NOS3 generates ROS rather than NO ADDIN REFMGR.CITE Takimoto2005528Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure loadJournal528Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure loadTakimoto,E.Champion,H.C.Li,M.Ren,S.Rodriguez,E.R.Tavazzi,B.Lazzarino,G.Paolocci,N.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/5analogs & derivativesAnimalsBiopterinCardiologyCardiomegalyenzymologyfibrosishearthypertrophyImmunoblottingmetabolismMicenitric oxideNitric Oxide SynthaseNitric Oxide Synthase Type IINitric Oxide Synthase Type IIINOOxidative Stressphysiologyreactive oxygen speciesremodelingStressVentricular Dysfunction,LeftNot in File12211231J.Clin.Invest.1155Journal of Clinical InvestigationJ.Clin.Invest.141. The cellular signal transduction pathways of ROS and RNS are tightly intertwined and complex, and beyond the scope of this review. Heart failure is not only associated with excessive ROS production, but also with a failing defense against ROS through dow n r e g u l a t i o n o f P P A R a n d s u b s e q u e n t d e c r e a s e d s u p e r o x i d e d i s m u t a s e e x p r e s s i o n A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > G u e l l i c h < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 7 5 5 < / R e c N u m > < I D T e x t > R o l e o f o x i d a t i v e s t r e s s i n c a r d i a c d y s f u n c t i o n o f P P A R { a l p h a } - / - m i c e < / I D Text>Journal755Role of oxidative stress in cardiac dysfunction of PPAR{alpha}-/- miceGuellich,AzizDamy,ThibaudLecarpentier,YvesConti,MarcClaes,VictorSamuel,Jane LyseQuillard,JeanineHebert,Jean LouisPineau,ThierryCoirault,Catherine2007/7/1analysisdeficiencyechocardiographyGlutathioneMicemuscleNOOxidative StressStressSuperoxide DismutaseNot in FileH93102Am J Physiol Heart Circ Physiol2931http://ajpheart.physiology.org/cgi/content/abstract/293/1/H93AJP - Heart and Circulatory PhysiologyAm J Physiol Heart Circ Physiol179.
ROS reduce myocyte contractility through suppression of enzymes involved in excitation-contraction coupling (LTCCs ADDIN REFMGR.CITE Kaplan2003432Free radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulumJournal432Free radical-induced protein modification and inhibition of Ca2+-ATPase of cardiac sarcoplasmic reticulumKaplan,P.Babusikova,E.Lehotsky,J.Dobrota,D.2003/6Adenosine TriphosphatasesAmino Acidsanalogs & derivativesAnimalsAntioxidantscalciumCalcium-Transporting ATPaseschemistryDose-Response Relationship,DrugEdetic AcidFree RadicalsKineticsLipid MetabolismLipid PeroxidationLysinemetabolismMyocardiumOxidative StressOxygenpharmacologyRatsSarcoplasmic ReticulumSpectrometry,FluorescenceTime FactorsTryptophanTyrosineNot in File4147Mol.Cell Biochem.2481-2Mol.Cell Biochem.1230 and SERCA ADDIN REFMGR.CITE Nakaya1992433Mechanism of the membrane depolarization induced by oxidative stress in guinea-pig ventricular cellsJournal433Mechanism of the membrane depolarization induced by oxidative stress in guinea-pig ventricular cellsNakaya,H.Takeda,Y.Tohse,N.Kanno,M.1992/5AnimalsArrhythmiaBenzene DerivativescalciumCell Membranecytologydrug effectsFemaleGuinea PigsHeart VentriclesMaleMembrane PotentialsmetabolismmuscleMusclesOxidative StressOxygenPapillary MusclespharmacologyphysiologyPotassium ChannelsNot in File523534J.Mol.Cell Cardiol.245J.Mol.Cell Cardiol.1231, see online supplement). Polynitrosylation of the Ryanodine receptor (RyR; see online supplement for a comparable mechanism involving hyperphosphorylation of the RyR by protein kinase A, PKA) can further contribute to contractile dysfunction ADDIN REFMGR.CITE Xu1998440Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylationJournal440Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylationXu,L.Eu,J.P.Meissner,G.Stamler,J.S.1998/1/9analogs & derivativesAnimalscalciumCyclic GMPCysteineDithiothreitolDogsdrug effectsElectric ConductivityEthylmaleimideGlutathioneion channelIon ChannelsLiposomesMercaptoethanolmetabolismMolsidomineMyocardiumnitric oxideNitrosationNitroso CompoundsNOOxidation-ReductionpharmacologyProteolipidsRyanodine Receptor Calcium Release ChannelS-NitrosoglutathioneS-NitrosothiolsSulfhydryl CompoundsNot in File234237Science.2795348Science. < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 2 3 2 . M a n y s i g n a l i n g m o l e c u l e s ( e . g . A T I I , T G F 1 , P D G F , T N F a n d E T - 1 ) u s e R O S f o r m a t i o n t o i n d u c e h y p e r t r o p h i c p a t h w a y s ( i n v o l v i n g M A P K s , P K C , c a l c i n e u r i n , A k t 1 , S r c ) , w h i l e R O S f o r m a t i o n i s accompanied by side-effects of inflammation, cell damage and enzyme inactivation ADDIN REFMGR.CITE Giordano2005428Oxygen, oxidative stress, hypoxia, and heart failureJournal428Oxygen, oxidative stress, hypoxia, and heart failureGiordano,F.J.2005/3AnimalsAnoxiacalciumCardiac Output,LowcytologyEnergy MetabolismGene ExpressionGene Expression Regulationheartheart failureHumanshypertrophyhypoxiaIon ChannelsLipidsmetabolismmitochondriaMyocardial IschemiaMyocardiumOxidative StressOxygenpathologyphysiologyphysiopathologyreactive oxygen speciesSignal TransductiontoxicityNot in File500508J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1212. ATII induces ROS via NAD(P)H oxidases, an effect that seems to be mediated by rho activation since it can be blocked by HMG-CoA reductase inhibitors (statins) ADDIN REFMGR.CITE Takemoto2001430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyJournal430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyTakemoto,M.Node,K.Nakagami,H.Liao,Y.Grimm,M.Takemoto,Y.Kitakaze,M.Liao,J.K.2001/11Angiotensin IIAnimalsAntioxidantsAtrial Natriuretic FactorCardiomegalyCells,Cultureddrug effectsgeneticshearthypertrophyLeucinemetabolismMicemortalityMyocardiumNOOxidation-Reductionpharmacologyphysiologyprevention & controlPromoter Regions (Genetics)rac1 GTP-Binding ProteinRatsRats,Sprague-DawleyRhosimvastatinstatinSuperoxidestherapyNot in File14291437J.Clin.Invest.10810Journal of Clinical InvestigationJ.Clin.Invest.135. ROS have been implicated in cardiac remodeling after ischemia through activation of matrix metalloproteinases (MMPs) ADDIN REFMGR.CITE Mann1998429Activation of matrix metalloproteinases in the failing human heart: breaking the tie that bindsJournal429Activation of matrix metalloproteinases in the failing human heart: breaking the tie that bindsMann,D.L.Spinale,F.G.1998/10/27Cardiac Output,LowEnzyme ActivationenzymologyExtracellular MatrixheartHumansMatrix MetalloproteinasesmetabolismMetalloendopeptidasesphysiologyTissue Inhibitor of MetalloproteinasesVentricular RemodelingNot in File16991702Circulation.9817Circulation.1233. In the overloaded heart, ROS can induce both adaptive hypertrophy and apoptosis; the level of ROS produced seems to determine the direction of the response, since relatively low levels are associated with ERK1/2 activation related protein synthesis, whereas higher levels activate pro-apoptotic pathways (via p38 and JNK, see online supplement for details on MAPK signaling) ADDIN REFMGR.CITE Kwon2003431H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathwaysJournal431H(2)O(2) regulates cardiac myocyte phenotype via concentration-dependent activation of distinct kinase pathwaysKwon,S.H.Pimentel,D.R.Remondino,A.Sawyer,D.B.Colucci,W.S.2003/6AdenoviridaeAdultAnimalsapoptosisBlotting,WesternCell SurvivalchemistryDose-Response Relationship,DruggeneticsHydrogen PeroxidehypertrophyIn Situ Nick-End LabelingLeucineMalemetabolismMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Mitogen-Activated Protein KinasesMuscle CellsMyocardiumNecrosisOxygenp38 Mitogen-Activated Protein KinasespharmacologyPhenotypeRatsRats,Sprague-Dawleyreactive oxygen speciesSignal TransductionsurvivalNot in File615621J.Mol.Cell Cardiol.356J.Mol.Cell Cardiol.1234. It is unclear whether S-nitrosylation exerts mainly anti-apoptotic effec t s ( e . g . b y S - n i t r o s y l a t i n g a n d t h e r e f o r e i n h i b i t i n g c a s p a s e s 3 a n d 9 , J N K a n d A S K - 1 ; s e e o n l i n e s u p p l e m e n t ) o r p r o - a p o p t o t i c e f f e c t s ( e . g . b y S - n i t r o s y l a t i n g a n d t h e r e f o r e i n h i b i t i n g N F - B ) A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > H a r e < / A u t h o r > < Y e a r > 2 0 0 5 438NO/redox disequilibrium in the failing heart and cardiovascular systemJournal438NO/redox disequilibrium in the failing heart and cardiovascular systemHare,J.M.Stamler,J.S.2005/3adverse effectsAnimalsbloodCardiac Output,LowCardiologyCardiovascular AgentsCardiovascular Systemcytologydrug therapyheartHomeostasisHumansmetabolismMyocardiumnitric oxideOxidation-ReductionOxygenpathologyPhenotypephysiologyphysiopathologyReactive Nitrogen Speciesreactive oxygen speciesSignal Transductiontherapeutic useNot in File509517J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1149.
5. Heart failure and Immune Cells
In conditions of ischemia/reperfusion, macrophages recruit neutrophils through the secretion of IL-6, and neutrophils contribute to tissue injury ADDIN REFMGR.CITE Youker1992500Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusionJournal500Neutrophil adherence to isolated adult cardiac myocytes. Induction by cardiac lymph collected during ischemia and reperfusionYouker,K.Smith,C.W.Anderson,D.C.Miller,D.Michael,L.H.Rossen,R.D.Entman,M.L.1992/2AdultAnimalsantibodiesCell AdhesionCell Adhesion MoleculesCoronary DiseaseCytokinesDogsFemaleIL-6Intercellular Adhesion Molecule-1Interleukin-1Interleukin-6ischemiaLymphMacrophage-1 AntigenMaleMyocardial Reperfusion InjuryMyocardiumNecrosisNeutrophilspathologyphysiologyTumor Necrosis Factor-alphaNot in File602609J.Clin.Invest.892Journal of Clinical InvestigationJ.Clin.Invest.1235. Various cell types exert a direct or indirect influence on the composition of the extracellular matrix. Macrophages, present in greater numbers in failing than in normal human hearts ADDIN REFMGR.CITE Azzawi2005501The distribution of cardiac macrophages in myocardial ischaemia and cardiomyopathyJournal501The distribution of cardiac macrophages in myocardial ischaemia and cardiomyopathyAzzawi,M.Kan,S.W.Hillier,V.Yonan,N.Hutchinson,I.V.Hasleton,P.S.2005/3AdolescentAdultanalysisAntigens,Differentiation,MyelomonocyticAntigens,CDbloodBlood VesselsCardiomyopathiesCardiomyopathy,DilatedchemistryFemaleheartHeart TransplantationHumansImmunohistochemistryMacrophagesMalemetabolismmethodsMiddle AgedMyocardial IschemiaMyocardiumpathologyNot in File314319Histopathology.463Histopathology.1236, are recruited by monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule-1, and contribute to remodeling throug h s e c r e t i o n o f T G F - A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > K a i < / A u t h o r > < Y e a r > 2 0 0 5 < / Y e a r > < R e c N u m > 5 0 2 < / R e c N u m > < I D T e x t > D i a s t o l i c d y s f u n c t i o n i n h y p e r t e n s i v e h e a r t s : r o l e s o f p e r i v a s c u l a r i n f l a m m a t i o n a n d r e a c t i v e m y o c a r d i a l f i b r o s i s < / I D T e x t > < M D L R e f _ T y p e = "Journal">Journal502Diastolic dysfunction in hypertensive hearts: roles of perivascular inflammation and reactive myocardial fibrosisKai,H.Kuwahara,F.Tokuda,K.Imaizumi,T.2005/6AnimalsbloodBlood PressureCoronary CirculationDiastolediastolic functionfibrosisheartheart failureHumanshypertrophyimmunologyinflammationIntercellular Adhesion Molecule-1MCP-1modelmyocardial fibrosisMyocardiumpathologyphysiologyphysiopathologyRatsResearchVasculitisVentricular Dysfunction,LeftNot in File483490Hypertens.Res.286Hypertens.Res.1237. Mast cell density is increased in pressure overloaded ventricles and these cells can activate fibroblasts, MMPs and proteases ADDIN REFMGR.CITE Janicki2006503Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overloadJournal503Cardiac mast cell regulation of matrix metalloproteinase-related ventricular remodeling in chronic pressure or volume overloadJanicki,J.S.Brower,G.L.Gardner,J.D.Forman,M.F.Stewart,J.A.,Jr.Murray,D.B.Chancey,A.L.2006/2/15CardiomyopathiesCollagenenzymologyExtracellular Matrixheartheart failureHeart Failure,CongestiveHumansHypertensionhypertrophyimmunologyMast CellsMatrix MetalloproteinasesmetabolismMyocardial InfarctionMyocardiumremodelingreviewStressTissue Inhibitor of MetalloproteinasesVentricular PressureVentricular RemodelingNot in File657665Cardiovasc.Res.693Cardiovasc.Res.1238. T-helper (CD4+) lymphocytes interact with cardiac fibroblasts and are essential components in the cardiac remodeling process ADDIN REFMGR.CITE Yu2005497A role for T lymphocytes in mediating cardiac diastolic functionJournal497A role for T lymphocytes in mediating cardiac diastolic functionYu,Q.Watson,R.R.Marchalonis,J.J.Larson,D.F.2005/8AnimalschemistryCoculture TechniquesCollagenDiastolediastolic functionExtracellular MatrixFemalefibroblastFibroblastsGene Expressiongeneticsheartheart failureImmune SystemimmunologyLeukemia Virus,MurineMatrix MetalloproteinasesmetabolismMiceMice,Inbred C57BLMyocardiumPeptide FragmentspharmacologyPhenotypephysiologyphysiopathologyProcollagenProtein PrecursorsReceptors,Antigen,T-Cell,alpha-betaremodelingRetroviridae InfectionsRNA,MessengerStressT-lymphocyteTh1 CellsTh2 CellsVariation (Genetics)Not in FileH643H651Am.J.Physiol Heart Circ.Physiol.2892Am.J.Physiol Heart Circ.Physiol.1Yu2006498Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodelingJournal498Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodelingYu,Q.Horak,K.Larson,D.F.2006/7Amino Acid OxidoreductasesAnimalsbloodBlood Pressurechemically inducedchemistryCollagencomplicationsDisease Models,Animaldrug effectsExtracellular MatrixFemaleGene ExpressiongeneticsheartHypertensionimmunologymetabolismMiceMice,Inbred BALB CMice,ScidMice,Inbred C57BLNG-Nitroarginine Methyl EsterpharmacologyphysiologyremodelingSpecies SpecificitysurgeryT-lymphocyteT-LymphocytesVentricular Function,LeftVentricular RemodelingNot in File98104Hypertension.481Hypertension. < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 2 3 9 ; 2 4 0 . F i n a l l y , B - c e l l s m a y c o n t r i b u t e t o t h e d e v e l o p m e n t o f h e a r t f a i l u r e b y t h e s e c r e t i o n o f a u t o - a n t i b o d i e s a g a i n s t m i t o c h o n d r i a l p r o t e i n s , c o n t r a c t i l e p r o t e i n s , c a r d i a c 1 - r e c eptors and muscarinergic receptors; such antibodies have been demonstrated in dilated cardiomyopathy ADDIN REFMGR.CITE Schulze1990492Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac functionJournal492Antibodies to ADP-ATP carrier--an autoantigen in myocarditis and dilated cardiomyopathy--impair cardiac functionSchulze,K.Becker,B.F.Schauer,R.Schultheiss,H.P.1990/3AdenosineAnimalsantibodiesAutoantibodiesAutoantigensBlotting,WesterncalciumCardiomyopathiesCardiomyopathy,DilatedEnergy MetabolismFemaleGuinea PigsheartImmunizationimmunologylactatemetabolismMitochondrial ADP,ATP TranslocasesMyocardial ContractionMyocarditisMyocardiumNucleotidyltransferasesOxygenOxygen ConsumptionPhosphorylationphysiologyphysiopathologyRadioimmunoassaystroke volumeNot in File959969Circulation.813Circulation.1Caforio1992493Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathyJournal493Identification of alpha- and beta-cardiac myosin heavy chain isoforms as major autoantigens in dilated cardiomyopathyCaforio,A.L.Grazzini,M.Mann,J.M.Keeling,P.J.Bottazzo,G.F.McKenna,W.J.Schiaffino,S.1992/5AdultAgedantibodiesAutoantibodiesAutoantigensCardiomyopathiesCardiomyopathy,DilatedchemistryElectrophoresisenzymologyFemaleFluorescent Antibody TechniqueheartHumansImmunizationImmunoblottingimmunologyMalemethodsMiceMiddle AgedmodelMyofibrilsMyosinsSodiumNot in File17341742Circulation.855Circulation.1Limas1989494Autoantibodies against beta-adrenoceptors in human idiopathic dilated cardiomyopathyJournal494Autoantibodies against beta-adrenoceptors in human idiopathic dilated cardiomyopathyLimas,C.J.Goldenberg,I.F.Limas,C.1989/1Adenylate CyclaseAdultAgedanalysisAnimalsantagonists & inhibitorsAutoantibodiesbloodCardiomyopathiesCardiomyopathy,DilatedCoronary DiseaseDihydroalprenololenzymologyheartHeart Valve DiseasesHumansImmunoglobulin GimmunologyLungmetabolismMiddle AgedMyocardiumNONorepinephrinepharmacologyRatsReceptors,Adrenergic,betaNot in File97103Circ.Res.641Circ.Res.1Magnusson1994495Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effectJournal495Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effectMagnusson,Y.Wallukat,G.Waagstein,F.Hjalmarson,A.Hoebeke,J.1994/6AgedAmino Acid SequenceAnimalsantibodiesAutoantibodiesAutoimmunityCardiomyopathiesCardiomyopathy,DilatedCyclic AMPDose-Response Relationship,ImmunologicFemaleheartheart rateHumansimmunologyIsoproterenolMalemethodsMiddle AgedMolecular Sequence DataNOphysiologyRabbitsRatsRats,WistarReceptors,Adrenergic,beta-1ResearchNot in File27602767Circulation.896Circulation.1Fu1993496Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathyJournal496Localization of a functional autoimmune epitope on the muscarinic acetylcholine receptor-2 in patients with idiopathic dilated cardiomyopathyFu,L.X.Magnusson,Y.Bergh,C.H.Liljeqvist,J.A.Waagstein,F.Hjalmarson,A.Hoebeke,J.1993/5AdultAmino Acid SequenceAnimalsAutoantibodiesbloodCardiomyopathiesCardiomyopathy,DilatedCell Membranechemical synthesisdrug effectsEnzyme-Linked Immunosorbent AssayEpitopesFemaleGuanylyl ImidodiphosphateHumansImmunoblottingimmunologyisolation & purificationKineticsMalemetabolismMiddle AgedMolecular Sequence DataMyocardiumNOPeptidespharmacologyQuinuclidinyl BenzilateRatsReceptors,Adrenergic,betaReceptors,MuscarinicReference ValuesNot in File19641968J.Clin.Invest.915Journal of Clinical InvestigationJ.Clin.Invest.1Goser2006565Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardiumJournal565Cardiac troponin I but not cardiac troponin T induces severe autoimmune inflammation in the myocardiumGoser,S.Andrassy,M.Buss,S.J.Leuschner,F.Volz,C.H.Ottl,R.Zittrich,S.Blaudeck,N.Hardt,S.E.Pfitzer,G.Rose,N.R.Katus,H.A.Kaya,Z.2006/10/17AnimalsAutoimmune DiseasesbloodCardiomegalyclassificationclinicaldiagnosisFemalefibrosisheartheart failureimmunologyinflammationMalemethodsMiceMice,Inbred BALB CmortalityMyocarditisMyocardiumNORiskSensitivity and SpecificitySyndrometoxicitytroponinTroponin ITroponin TNot in File16931702Circulation.11416Circulation.1241-246. It is unclear whether these antibodies play a role in the initiation or propagation of the disorder, whether they are formed in response to tissue injury, and whether they and the cytokines discussed above could play a role in right heart failure.
6. Cardiac hypoxia contributing to the transition from compensated hypertrophy to dilatation and failure
Hypoxia-indu c i b l e f a c t o r 1
E x p r e s s i o n o f H I F - 1 i n c a r d i o m y o c y t e s i s r e q u i r e d t o m a i n t a i n n o r m a l m y o c a r d i a l m e t a b o l i s m , v a s c u l a r i t y , c a l c i u m h a n d l i n g a n d c o n t r a c t i l e f u n c t i o n A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > H u a n g < / A u t h o r > < Y e a r > 2 0 0 4 < / Y e a r > < R e c N u m > 4 3 7 < / R e c N u m>Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heartJournal437Cardiac myocyte-specific HIF-1alpha deletion alters vascularization, energy availability, calcium flux, and contractility in the normoxic heartHuang,Y.Hickey,R.P.Yeh,J.L.Liu,D.Dadak,A.Young,L.H.Johnson,R.S.Giordano,F.J.2004/7AnimalsapoptosisbiosynthesiscalciumCalcium SignalingCardiomyopathiescontractilityCoronary CirculationdeficiencyDNA-Binding ProteinsEnergy MetabolismGene DeletionGene ExpressionGene Expression RegulationgeneticsheartHeart Function TestsHIF-1alphaHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1,alpha SubunitlactatemetabolismMiceMice,Inbred C57BLMice,KnockoutmuscleMyocardial ContractionMyocardiumMyocytes,CardiacNecrosisNeovascularization,PhysiologicNuclear ProteinsOxygenOxygen Consumptionoxygen deliverypathologyphysiologyReverse Transcriptase Polymerase Chain ReactionRNA,MessengersurvivalTranscription FactorsTranscription,GeneticNot in File11381140FASEB J.1810The FASEB Journal < f n a m e = " S y s t e m " > F A S E B J . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 2 1 1 . M y o c a r d i a l H I F - 1 l e v e l s a r e u p r e g u l a t e d i n p a t i e n t s w i t h i s c h e m i c c a r d i o m y o p a t h y a n d a l t h o u g h m o s t e f f e c t s a r e o b v i o u s l y b e n e f i c i a l ( i n d u c t i o n o f a n g i o g e n e s i s , f a c i l i t a t i o n o f g l u c o s e u p t a k e a n d m e t a b o l i s m ) , i t h a s b e e n s p e c u l a t e d t h a t c h r o n i c a c t i v a t i o n o f H I F - 1 c o u l d b e d e l e t e r i o u s d u e t o i n d u c t i o n o f o x i d a t i v e s t r e s s , A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > G i o r d a n o < / A u t h o r > < Y e a r > 2 0 0 5 < / Year>428Oxygen, oxidative stress, hypoxia, and heart failureJournal428Oxygen, oxidative stress, hypoxia, and heart failureGiordano,F.J.2005/3AnimalsAnoxiacalciumCardiac Output,LowcytologyEnergy MetabolismGene ExpressionGene Expression Regulationheartheart failureHumanshypertrophyhypoxiaIon ChannelsLipidsmetabolismmitochondriaMyocardial IschemiaMyocardiumOxidative StressOxygenpathologyphysiologyphysiopathologyreactive oxygen speciesSignal TransductiontoxicityNot in File500508J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest. < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 2 1 2 b u t d a t a a r e l a c k i n g .
M i s m a t c h b e t w e e n m y o c a r d i a l o x y g e n d e l i v e r y a n d d e m a n d r e s u l t s i n e n h a n c e d s i g n a l i n g t h r o u g h t h e b a s i c h e l i x - l o o p - h e l i x t r a n s c r i p t i o n f a c t o r H I F - 1 ( s e e H Y P E R L I N K " f i le:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e4.ppt"fig. e4 and HYPERLINK "file:///\\\\Ns1\\intmed\\PULM\\HOME\\hjbogaard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e5.ppt"fig. e5). H I F - 1 i s c o n s t i t u t i v e l y t r a n s c r i b e d a n d t r a n s l a t e d , b u t u n d e r c o n d i t i o n s i n w h i c h o x y g e n i s a b u n d a n t i t u n d e r g o e s p r o t e o s o m a l d e g r a d a t i o n A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > S e m e n z a < / A u t h o r > < Y e a r > 2 0 0 1 < / Y e a r > < R e c N u m > 4 3 6 < / R e c N u m > < I D T e x t > H I F - 1 , O 2 , a n d the 3 PHDs: how animal cells signal hypoxia to the nucleusJournal436HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleusSemenza,G.L.2001/10/5AnimalsCaenorhabditis elegans ProteinsCell HypoxiaCell NucleusDNA-Binding ProteinsGene ExpressionGene Expression RegulationgeneticsHelminth ProteinsHomeostasisHumanshypoxiaHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1,alpha SubunitmetabolismNuclear ProteinsOxygenphysiologyProcollagen-Proline DioxygenaseSignal TransductionTranscription FactorsNot in File13Cell.1071Cell.1213. Under s u c h c o n d i t i o n s , c e l l u l a r p r o l y l - h y d r o x y l a s e s h y d r o x y l a t e H I F - 1 , p r o d u c i n g a b i n d i n g s i t e o n t h e H I F - 1 m o l e c u l e f o r t h e v o n H i p p e l - L i n d a u p r o t e i n ( V H L ) . V H L i s p a r t o f a u b i q u i t i n l i g a s e c o m p l e x t h a t p o l y u b i q u i t i n a t e s H I F - 1 a n d t a r g e t s i t f o r r a p i d d e s t r uction by the proteosome ADDIN REFMGR.CITE Semenza2001436HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleusJournal436HIF-1, O2, and the 3 PHDs: how animal cells signal hypoxia to the nucleusSemenza,G.L.2001/10/5AnimalsCaenorhabditis elegans ProteinsCell HypoxiaCell NucleusDNA-Binding ProteinsGene ExpressionGene Expression RegulationgeneticsHelminth ProteinsHomeostasisHumanshypoxiaHypoxia-Inducible Factor 1Hypoxia-Inducible Factor 1,alpha SubunitmetabolismNuclear ProteinsOxygenphysiologyProcollagen-Proline DioxygenaseSignal TransductionTranscription FactorsNot in File13Cell.1071Cell.1 2 1 3 . U n d e r h y p o x i c c i r c u m s t a n c e s , H I F - 1 i s n o t h y d r o x y l a t e d a n d r e g u l a t e s t h e t r a n s c r i p t i o n o f a n e x t e n s i v e r e p e r t o i r e o f g e n e s i n v o l v e d i n a n g i o g e n e s i s ( V E G F , A M ) , v a s c u l a r r e m o d e l i n g , e r y t h r o p o i e s i s ( e r y t h r o p o i e t i n , E P O ) , m e t a b o l i s m , a p o p t o s i s , r eactive oxygen species (ROS) formation, vascular tone and inflammation ADDIN REFMGR.CITE Giordano2005428Oxygen, oxidative stress, hypoxia, and heart failureJournal428Oxygen, oxidative stress, hypoxia, and heart failureGiordano,F.J.2005/3AnimalsAnoxiacalciumCardiac Output,LowcytologyEnergy MetabolismGene ExpressionGene Expression Regulationheartheart failureHumanshypertrophyhypoxiaIon ChannelsLipidsmetabolismmitochondriaMyocardial IschemiaMyocardiumOxidative StressOxygenpathologyphysiologyphysiopathologyreactive oxygen speciesSignal TransductiontoxicityNot in File500508J.Clin.Invest.1153Journal of Clinical InvestigationJ.Clin.Invest.1212. Additional non-oxygen dependent regulation of H I F - 1 e x p r e s s i o n o c c u r s v i a t h e t u m o r - s u p p r e s s o r p r o t e i n p 5 3 , i n t r a c e l l u l a r c o n c e n t r a t i o n s o f c o p p e r ( C u ) , A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > S a n o < / A u t h o r > < Y e a r > 2 0 0 7 < / Y e a r > < R e c N u m > 5 2 3 < / R e c N u m > < I D T e x t > p 5 3 - i n d u c e d i n h i b i t i o n o f H i f - 1 c a u s e s c a r d i a c d y s function during pressure overloadJournal523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadSano,M.Minamino,T.Toko,H.Miyauchi,H.Orimo,M.Qin,Y.Akazawa,H.Tateno,K.Kayama,Y.Harada,M.Shimizu,I.Asahara,T.Hamada,H.Tomita,S.Molkentin,J.D.Zou,Y.Komuro,I.2007/3/22Animalsantagonists & inhibitorsAortaBlood PressureCardiac Output,LowCardiomegalyCoronary CirculationDisease Progressiongeneticsheartheart failurehypertrophyHypoxia-Inducible Factor 1,alpha SubunitmetabolismMiceNeovascularization,PathologicpathologyphysiopathologyTumor Suppressor Protein p53Not in File444448Nature.4467134Nature.1Jiang2007525Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in miceJournal525Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in miceJiang,Y.Reynolds,C.Xiao,C.Feng,W.Zhou,Z.Rodriguez,W.Tyagi,S.C.Eaton,J.W.Saari,J.T.Kang,Y.J.2007/3AnimalsantibodiesCardiomyopathiesCardiomyopathy,HypertrophicCells,CulturedChronic DiseasecomplicationsCopperdiet therapyDietary SupplementsDisease Models,Animaletiologyheartheart failureHIF-1alphaHumansHypertensionhypertrophyMaleMiceMice,Inbred C57BLmodelphysiopathologytherapeutic useVEGFNot in File657666J.Exp.Med.2043The Journal of Experimental MedicineJ.Exp.Med.150;54 and, as recently shown in cancer research , v i a c o m p e t i o n w i t h T c f / L e f f o r b i n d i n g w i t h - c a t e n i n w i t h i n t h e n u c l e u s ( s e e H Y P E R L I N K " f i l e : / / / \ \ \ \ N s 1 \ \ i n t m e d \ \ P U L M \ \ H O M E \ \ h j b o g a a r d \ \ R H F i n P A H % 2 0 R e v i e w \ \ S u b m i s s i o n % 2 0 C h e s t \ \ P a r t I \ \ F i g u r e % 2 0 e 4 . p p t " f i g . e 4 ) . I n h y p o x i c c o n d i t i o n s , b i n d i n g t o H I F - 1 i s m o r e p r e v a l e n t a n d i n d u c t i o n o f c e l l c y c l e a r r e s t f o l l o w s , t o g e t h e r w i t h t r a n s c r i p t i o n o f a n g i o g e n i c g r o w t h f a c t o r s . I n n o r m o x i c c o n d i t i o n s a n d w h e n W n t / F z s i g n a l i n g i s a c t i v e , - c a t e n i n b i n d i n g t o T c f / L e f p r e v a i l s a n d h y p e r t r o p h i c a n d p r o l i f e r a t i v e g r o wth factors are activated ADDIN REFMGR.CITE Kaidi2007737Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxiaJournal737Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxiaKaidi,A.Williams,A.C.Paraskeva,C.2007/2Adaptation,PhysiologicalAnoxiabeta CateninCell Line,TumorCell ProliferationCell SurvivalCell Transformation,NeoplasticColonic NeoplasmsGenesHIF-1alphaHumanshypoxiaHypoxia-Inducible Factor 1metabolismResearchSignal TransductionsurvivalNot in File210217Nat.Cell Biol.92Nat.Cell Biol.1196. It would be very interesting to know whether this mechanism plays a role in the cardiac hypertrophic response as well. It is likely that the role of the Wnt pathway in cardiac hypertrophy will become clearer in the near future.
Vascular endothelial growth factor
VEGF signaling is initially upregulated in the LV exposed to TAC, but after two weeks insufficient VEGF signaling contributes to decreased cardiac microvascular density and systolic dysfunction. Restoring VEGF signaling leads to an increase in capillary density and an improvement in systolic function ADDIN REFMGR.CITE Sano2007523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadJournal523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadSano,M.Minamino,T.Toko,H.Miyauchi,H.Orimo,M.Qin,Y.Akazawa,H.Tateno,K.Kayama,Y.Harada,M.Shimizu,I.Asahara,T.Hamada,H.Tomita,S.Molkentin,J.D.Zou,Y.Komuro,I.2007/3/22Animalsantagonists & inhibitorsAortaBlood PressureCardiac Output,LowCardiomegalyCoronary CirculationDisease Progressiongeneticsheartheart failurehypertrophyHypoxia-Inducible Factor 1,alpha SubunitmetabolismMiceNeovascularization,PathologicpathologyphysiopathologyTumor Suppressor Protein p53Not in File444448Nature.4467134Nature. < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 5 0 . T h e e x p l a n a t i o n f o r t h i s b i p h a s i c r e s p o n s e o f V E G F p r o t e i n e x p r e s s i o n m a y r e s i d e i n a n A k t 1 - p 5 3 - H I F - 1 s i g n a l i n g a x i s ( s e e H Y P E R L I N K " f i l e : / / / \ \ \ \ N s 1 \ \ i n t m e d \ \ P U L M \ \ H O M E \ \ h j b o g a ard\\RHFinPAH%20Review\\Submission%20Chest\\PartI\\Figure%20e5.ppt"fig. e5). Short-term activation of Akt1 leads to adaptive cardiac hypertrophy together with increased cardiac myocyte VEGF secretion and angiogenesis, while chronic Akt1 activation is associated with cardiac dilatation, a decreased secretion of VEGF and a reduced capillary density ADDIN REFMGR.CITE Shiojima2005570Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failureJournal570Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failureShiojima,I.Sato,K.Izumiya,Y.Schiekofer,S.Ito,M.Liao,R.Colucci,W.S.Walsh,K.2005/8Angiopoietin-2AnimalsbiosynthesisCapillariesCardiologyCardiomyopathiesCardiomyopathy,DilatedcontractilityenzymologyGene Expression Regulationgeneticsgrowth & developmentheartheart failureHeart Failure,CongestiveHumanshypertrophymetabolismMiceMice,TransgenicMyocardiumNeovascularization,PathologicpathologyProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktremodelingVascular Endothelial Growth Factor AVEGFVentricular RemodelingNot in File21082118J.Clin.Invest.1158Journal of Clinical InvestigationJ.Clin.I n v e s t . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 1 7 4 . S i m i l a r l y , c h r o n i c p r e s s u r e o v e r l o a d l e a d s t o a c c u m u l a t i o n o f t h e t u m o r s u p p r e s s o r p 5 3 a n d , a s a c o n s e q u e n c e , d o w n r e g u l a t i o n o f H I F - 1 a n d V E G F . E i t h e r p r e v e n t i n g p53 accumulation or introducing adenoviral vectors encoding VEGF directly into the heart enhances the number of microvessels, facilitates myocardial hypertrophic growth and restores myocardial function ADDIN REFMGR.CITE Sano2007523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadJournal523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadSano,M.Minamino,T.Toko,H.Miyauchi,H.Orimo,M.Qin,Y.Akazawa,H.Tateno,K.Kayama,Y.Harada,M.Shimizu,I.Asahara,T.Hamada,H.Tomita,S.Molkentin,J.D.Zou,Y.Komuro,I.2007/3/22Animalsantagonists & inhibitorsAortaBlood PressureCardiac Output,LowCardiomegalyCoronary CirculationDisease Progressiongeneticsheartheart failurehypertrophyHypoxia-Inducible Factor 1,alpha SubunitmetabolismMiceNeovascularization,PathologicpathologyphysiopathologyTumor Suppressor Protein p53Not in File444448Nature.4467134Nature.150. This seems not to be a coincidence, since Akt1 and p53 signaling are highly interdependent ADDIN REFMGR.CITE Franke2003571PI3K/Akt and apoptosis: size mattersJournal571PI3K/Akt and apoptosis: size mattersFranke,T.F.Hornik,C.P.Segev,L.Shostak,G.A.Sugimoto,C.2003/12/81-Phosphatidylinositol 3-KinaseAnimalsapoptosisCell DeathCell SurvivalHumansMicemodelModels,AnimalModels,GeneticpharmacologyPhosphoric Monoester HydrolasesphysiologyProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseResearchSignal TransductionsurvivalTumor Suppressor Protein p53Tumor Suppressor ProteinsNot in File89838998Oncogene.2256Oncogene.1214. The importance of VEGF signaling in the hypertrophic response to pressure overload is further demonstrated by a study in mice exposed to TAC in which disruption of VEGF signaling led to the development of thin-walled, dilated and hypovascular hearts displaying contractile dysfunction ADDIN REFMGR.CITE Izumiya2006566Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overloadJournal566Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overloadIzumiya,Y.Shiojima,I.Sato,K.Sawyer,D.B.Colucci,W.S.Walsh,K.2006/5Adaptation,PhysiologicalAnimalsantagonists & inhibitorsAortaCapillariesCardiac Output,LowCardiomegalyCollagencomplicationsConstrictionCoronary CirculationechocardiographyetiologyfibrosisGene Transfer Techniquesgeneticsheartheart failureHypertensionhypertrophyImmunoglobulin Fc FragmentsMalemetabolismMiceMice,Inbred C57BLmodelMyocardial Contractionmyocardial fibrosisMyocardiumNOpathologyphysiopathologyUp-RegulationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2VEGFVentricular RemodelingNot in File887893Hypertension.475Hypertension.145. The exact mechanism by which VEGF influences cardiomyocyte hypertrophy is not known. Both indirect effects through secretion of paracrine factors (NO, ET-1, PGI2) by newly formed endothelial cells and direct activation of hypertrophic pathways (e.g. involving MAPKs) in the cardiomyocyte have been proposed ADDIN REFMGR.CITE Brutsaert2003567Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicityJournal567Cardiac endothelial-myocardial signaling: its role in cardiac growth, contractile performance, and rhythmicityBrutsaert,D.L.2003/1AdultangiopoietinAngiotensin IIAnimalsCapillariesEndocardiumEndothelial Cellsendotheliumgrowth & developmentheartheart rateHumansmetabolismMyocardial Contractionnitric oxidePhenotypephysiologyRiskRisk FactorsSignal TransductionsurvivalNot in File59115Physiol Rev.831Physiol Rev.1Seko1998569Vascular endothelial growth factor (VEGF) activates Raf-1, mitogen-activated protein (MAP) kinases, and S6 kinase (p90rsk) in cultured rat cardiac myocytesJournal569Vascular endothelial growth factor (VEGF) activates Raf-1, mitogen-activated protein (MAP) kinases, and S6 kinase (p90rsk) in cultured rat cardiac myocytesSeko,Y.Takahashi,N.Tobe,K.Ueki,K.Kadowaki,T.Yazaki,Y.1998/6Activating Transcription Factor 2analysisAnimalsAnimals,NewbornCells,CulturedCyclic AMP Response Element-Binding ProteincytologyEndothelial Growth FactorsEnzyme ActivationenzymologyfibroblastFibroblastsGene Expression RegulationgeneticshypoxiaLymphokinesmetabolismMyelin Basic ProteinsMyocardiumpharmacologyPhosphorylationphysiologyProtein-Serine-Threonine KinasesProto-Oncogene Proteins c-junRatsRats,WistarRNA,MessengerSignal TransductionStressTranscription FactorsVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVEGFNot in File239246J.Cell Physiol.1753J.Cell Physiol.1215;216. VEGF not only affects cardiomyocyte growth but also apoptosis, which can be prevented in rabbits exposed to pressure overload by intra-pericardial installation of VEGF ADDIN REFMGR.CITE Friehs2006568Vascular endothelial growth factor prevents apoptosis and preserves contractile function in hypertrophied infant heartJournal568Vascular endothelial growth factor prevents apoptosis and preserves contractile function in hypertrophied infant heartFriehs,I.Barillas,R.Vasilyev,N.V.Roy,N.McGowan,F.X.del Nido,P.J.2006/7/4AnimalsAnimals,NewbornAorta,ThoracicapoptosisCapillariesCardiomyopathy,HypertrophiccontractilityDisease Progressiondrug effectsDrug Evaluation,Preclinicaldrug therapyechocardiographyetiologygeneticsheartheart failurehypertrophyHypertrophy,Left VentricularImmunoblottingIn Situ Nick-End LabelingLigationmetabolismmethodsmodelMyocardial ContractionMyocardiumMyocytes,CardiacNeovascularization,PhysiologicpathologyPerfusionphysiopathologyPoly(ADP-ribose) PolymerasesRabbitsRecombinant Proteinssurgerysurvivaltherapeutic useVascular Endothelial Growth Factor AVEGFNot in FileI290I295Circulation.1141 SupplCirculation.1217. Another regulator of VEGF signaling is EPO. Recently, EPO receptors were demonstrated in the heart and disruption of cardiac EPO signaling accelerates the development of heart failure in mice subjected to TAC, which is associated with decreased VEGF signaling and capillary density ADDIN REFMGR.CITE Asaumi2007740Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in MiceJournal740Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in MiceAsaumi,YasuhideKagaya,YutakaTakeda,MorihikoYamaguchi,NobuhiroTada,HirokoIto,KentaOhta,JunShiroto,TakashiShirato,KunioMinegishi,NaokoShimokawa,Hiroaki2007/4/17CapillarieserythropoetinMiceMyocardiumTACVEGFNot in File20222032Circulation11515http://circ.ahajournals.org/cgi/content/abstract/115/15/2022Circulation160.
7. Cardiac cell loss, regeneration and cellular senescence in heart failure
Apoptosis
There are two pathways leading to apoptosis. The first pathway, in which caspases are activated via death receptors (e.g. Fas and TNF receptor) may be important in immune mediated heart failure, but does not seem to be important in more common forms of heart failure such as ischemic and dilated cardiomyopathy ADDIN REFMGR.CITE Kang2000540Apoptosis and heart failure: A critical review of the literatureJournal540Apoptosis and heart failure: A critical review of the literatureKang,P.M.Izumo,S.2000/6/9AnimalsapoptosisCardiac Output,Lowetiologyheartheart failureHumansphysiologyphysiopathologyreviewtherapyNot in File11071113Circ.Res.8611Circ.Res.1218. The second more important pathway in heart failure is the mitochondrial pathway, involving mitochondrial outer membrane permeabilization (MOMP) ADDIN REFMGR.CITE Kang2000540Apoptosis and heart failure: A critical review of the literatureJournal540Apoptosis and heart failure: A critical review of the literatureKang,P.M.Izumo,S.2000/6/9AnimalsapoptosisCardiac Output,Lowetiologyheartheart failureHumansphysiologyphysiopathologyreviewtherapyNot in File11071113Circ.Res.8611Circ.Res.1218. MOMP leads to cytosolic release of cytochrome c and other proteins that are normally found in between the mitochondrial outer and inner membrane. Subsequent to the release of cytochrome c, a self-amplifying caspase cascade is activated that ultimately leads to activation of caspase 3. Activated caspase 3 i n d u c e s n u c l e a r p r o t e i n c l e a v a g e a n d D N A f r a g m e n t a t i o n . O n e o f t h e p r o t e i n s t h a t a r e c l e a v e d i s - c a t e n i n ; c l e a v a g e i s l i k e l y n e c e s s a r y t o d i s m a n t l e c e l l - c e l l c o n t a c t s d u r i n g a p o p t o s i s A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > B r a n c o l i n i < / A u t h o r > < Y e a r > 1997692Dismantling cell-cell contacts during apoptosis is coupled to a caspase-dependent proteolytic cleavage of beta-cateninJournal692Dismantling cell-cell contacts during apoptosis is coupled to a caspase-dependent proteolytic cleavage of beta-cateninBrancolini,C.Lazarevic,D.Rodriguez,J.Schneider,C.1997/11/33T3 CellsActinsalpha CateninAnimalsapoptosisbeta CateninCaspase 3CaspasesCell CommunicationCell DeathCell LineCell SurvivalCisplatinCysteine EndopeptidasesCytoskeletal ProteinsCytoskeletonDogsdrug effectsHydrolysisKidneymetabolismMiceMicrofilamentsphysiologyProtein BindingProtein Processing,Post-Translationalradiation effectsSignal TransductiontoxicityTrans-ActivatorsUltraviolet RaysNot in File759771J Cell Biol.1393J Cell Biol.1219. The mitochondrial pathway is tightly regulated by the balance between anti-apoptotic proteins, such as Bcl-2, and pro-apoptotic proteins, such as Bax.
Caspase 3 induction of cardiomyocyte apoptosis is tightly related to rho signaling, with caspase 3 acting both up- and downstream of Rho kinase (ROCK, see online supplement). Chang et al. demonstrated that in the pathway leading to cardiomyocyte apoptosis, either induced by toxins or TAC, caspase 3 cleaves and activates ROCK, which generates a pro-apoptotic amplifying loop through activation of PTEN and subsequent inhibition of Akt1-mediated survival pathways ADDIN REFMGR.CITE Chang2006355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisJournal355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisChang,JiangXie,MinShah,Viraj R.Schneider,Michael D.Entman,Mark L.Wei,LeiSchwartz,Robert J.2006/9/26apoptosisheartheart failuremodelNot in File1449514500Proc.Natl.Acad.Sci.U.S.A.10339http://www.pnas.org/cgi/content/abstract/103/39/14495Proc.Natl.Acad.Sci.U.S.A.146. Del Re et al. confirmed this interaction and provided evidence for even more interaction between caspase 3 and ROCK. Activation of ROCK is associated with p53 mediated upregulation and activation of Bax, which subsequently translocates to the mitochondrial membrane to permeabilize it, releasing caspases ADDIN REFMGR.CITE Del Re2007713RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte ApoptosisJournal713RhoA/Rho Kinase Up-regulate Bax to Activate a Mitochondrial Death Pathway and Induce Cardiomyocyte ApoptosisDel Re,Dominic P.Miyamoto,ShigekiBrown,Joan Heller2007/3/16apoptosisCaspase 8Caspase 9Cell ProliferationCell SurvivalCytoskeletonDnaDNA FragmentationGene Expressionheartheart failurehypertrophymitochondriaRhosurvivalUp-RegulationNot in File80698078J.Biol.Chem.28211http://www.jbc.org/cgi/content/abstract/282/11/8069Journal of Biological ChemistryJ.Biol.Chem.1109.
Cardiomyocyte proliferation and senescence
It was calculated that the entire normal heart is replaced every 4.5 years; that is about 18 times over the human life span ADDIN REFMGR.CITE Anversa2006610Life and death of cardiac stem cells: a paradigm shift in cardiac biologyJournal610Life and death of cardiac stem cells: a paradigm shift in cardiac biologyAnversa,P.Kajstura,J.Leri,A.Bolli,R.2006/3/21AginganalysisAnimalsAntigens,LyapoptosisBiological MarkersCell AgingCell DivisionCell LineagechemistrycytologyDogsFetal Heartgrowth & developmentheartHomeostasisHumansMiceMultipotent Stem CellsMyocardial InfarctionMyocardiumMyocytes,CardiacpathologyphysiologyProto-Oncogene Proteins c-kitRatsResearchStem CellsNot in File14511463Circulation.11311Circulation.1220. The degree of cell loss is severely increased in heart failure (see above) and although the rate of myocyte formation is also increased, the pace of renewal is insufficient to prevent net cell loss ADDIN REFMGR.CITE Anversa2006610Life and death of cardiac stem cells: a paradigm shift in cardiac biologyJournal610Life and death of cardiac stem cells: a paradigm shift in cardiac biologyAnversa,P.Kajstura,J.Leri,A.Bolli,R.2006/3/21AginganalysisAnimalsAntigens,LyapoptosisBiological MarkersCell AgingCell DivisionCell LineagechemistrycytologyDogsFetal Heartgrowth & developmentheartHomeostasisHumansMiceMultipotent Stem CellsMyocardial InfarctionMyocardiumMyocytes,CardiacpathologyphysiologyProto-Oncogene Proteins c-kitRatsResearchStem CellsNot in File14511463Circulation.11311Circulation.1220. Since cardiac stem cells (CSCs) rarely divide, it is their progeny that actually replicates. High rates of cell turn-over do require repeated CSC division, however, which inevitably implies telomeric shortening and dysfunction, replicative senescence, cell death, reduction of the stem cell pool and exhaustion of the myocardial growth reserve ADDIN REFMGR.CITE Urbanek2003612Intense myocyte formation from cardiac stem cells in human cardiac hypertrophyJournal612Intense myocyte formation from cardiac stem cells in human cardiac hypertrophyUrbanek,K.Quaini,F.Tasca,G.Torella,D.Castaldo,C.Nadal-Ginard,B.Leri,A.Kajstura,J.Quaini,E.Anversa,P.2003/9/2AdultCardiomegalyCell DifferentiationCell DivisionFemaleHomeostasisHumanshypertrophyMalemetabolismMyocardiumMyocytes,CardiacpathologyphysiologyRegenerationStem CellsStressTelomeraseTelomereNot in File1044010445Proc.Natl.Acad.Sci.U.S.A.10018Proc.Natl.Acad.Sci.U.S.A.1Urbanek2005611Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failureJournal611Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failureUrbanek,K.Torella,D.Sheikh,F.De,Angelis A.Nurzynska,D.Silvestri,F.Beltrami,C.A.Bussani,R.Beltrami,A.P.Quaini,F.Bolli,R.Leri,A.Kajstura,J.Anversa,P.2005/6/14apoptosisBlotting,WesternCardiomyopathiesCell DifferentiationCell LineageCyclin-Dependent Kinase Inhibitor p16cytologyDNA-Binding Proteinsheartheart failureHumansIn Situ Hybridization,FluorescencemetabolismMitosisMultipotent Stem CellsmuscleMyocardial InfarctionMyocardiumphysiologyphysiopathologyRegenerationResearchStem CellsTelomeraseTelomereNot in File86928697Proc.Natl.Acad.Sci.U.S.A.10224Proc.Natl.Acad.Sci.U.S.A.1221;222. Telomeres are chromatin structures capping the ends of chromosomes that prevent the recognition of chromosomal ends as double-stranded DNA breaks, protecting these regions from recombination and degradation and avoiding a DNA damage cellular response. Telomeric DNA is composed of noncoding double-stranded G-rich tandem repeats that are extended several thousand base pairs. In human dividing cells including CSCs telomerase protects the integrity of the telomeric structure ADDIN REFMGR.CITE Blackburn2001613Switching and signaling at the telomereJournal613Switching and signaling at the telomereBlackburn,E.H.2001/9/21AnimalschemistryDnaDNA ReplicationDNA-Binding ProteinsgeneticsHumansmetabolismModels,GeneticphysiologyreviewSaccharomyces cerevisiaeSignal TransductionTelomeraseTelomereultrastructureNot in File661673Cell.1066Cell.1223. Upregulated telomerase activity in heart failure cannot prevent telomeric attrition, however, which fact may also be related to alterations in telomeric binding proteins (TRF-1 and 2, polymerase and many others) ADDIN REFMGR.CITE Chimenti2003614Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failureJournal614Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failureChimenti,C.Kajstura,J.Torella,D.Urbanek,K.Heleniak,H.Colussi,C.Di,Meglio F.Nadal-Ginard,B.Frustaci,A.Leri,A.Maseri,A.Anversa,P.2003/10/3AgedAged,80 and overAgingBiopsyCardiomyopathiesCardiomyopathy,DilatedCell AgingCell CycleCell Cycle ProteinsCell DeathCyclin-Dependent Kinase Inhibitor p16DNA-Binding ProteinsFemaleheartheart failureHeart Failure,CongestiveHumanshypertrophyMalemetabolismMicroscopy,ConfocalMitotic IndexMyocardiumMyocytes,CardiacNOpathologyRegenerationResearchSchizosaccharomyces pombe ProteinsTelomeraseTelomereVentricular FunctionNot in File604613Circ.Res.937Circ.Res.1Urbanek2005611Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failureJournal611Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failureUrbanek,K.Torella,D.Sheikh,F.De,Angelis A.Nurzynska,D.Silvestri,F.Beltrami,C.A.Bussani,R.Beltrami,A.P.Quaini,F.Bolli,R.Leri,A.Kajstura,J.Anversa,P.2005/6/14apoptosisBlotting,WesternCardiomyopathiesCell DifferentiationCell LineageCyclin-Dependent Kinase Inhibitor p16cytologyDNA-Binding Proteinsheartheart failureHumansIn Situ Hybridization,FluorescencemetabolismMitosisMultipotent Stem CellsmuscleMyocardial InfarctionMyocardiumphysiologyphysiopathologyRegenerationResearchStem CellsTelomeraseTelomereNot in File86928697Proc.Natl.Acad.Sci.U.S.A.10224Proc.Natl.Acad.Sci.U.S.A.1222;224. These events are accompanied by increased expression of p14ARF, p16 INK4a, p53 and phospho-p53, which together block the cell cycle, prohibit proliferation and activate the death program ADDIN REFMGR.CITE Anversa2006610Life and death of cardiac stem cells: a paradigm shift in cardiac biologyJournal610Life and death of cardiac stem cells: a paradigm shift in cardiac biologyAnversa,P.Kajstura,J.Leri,A.Bolli,R.2006/3/21AginganalysisAnimalsAntigens,LyapoptosisBiological MarkersCell AgingCell DivisionCell LineagechemistrycytologyDogsFetal Heartgrowth & developmentheartHomeostasisHumansMiceMultipotent Stem CellsMyocardial InfarctionMyocardiumMyocytes,CardiacpathologyphysiologyProto-Oncogene Proteins c-kitRatsResearchStem CellsNot in File14511463Circulation.11311Circulation.1220. Other consequences of cellular senescence that also affect mature cardiomyocytes are a reduced ability to synthesize hypertrophic proteins, decreased secretion of autocrine or paracrine factors and impaired antioxidant defense mechanisms ADDIN REFMGR.CITE Hasty2003616Aging and Genome Maintenance: Lessons from the Mouse?Journal616Aging and Genome Maintenance: Lessons from the Mouse?Hasty,PaulCampisi,JudithHoeijmakers,Janvan Steeg,HarryVijg,Jan2003/2/28AgingGenomeNot in File13551359Science2995611http://www.sciencemag.org/cgi/content/abstract/299/5611/1355Science1225. IGF-1 seems to protect aging CSCs and cardiomyocytes from senescence by phosphorylation of Akt1 which is associated with an increase in telomerase activity ADDIN REFMGR.CITE Torella2004615Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpressionJournal615Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpressionTorella,D.Rota,M.Nurzynska,D.Musso,E.Monsen,A.Shiraishi,I.Zias,E.Walsh,K.Rosenzweig,A.Sussman,M.A.Urbanek,K.Nadal-Ginard,B.Kajstura,J.Anversa,P.Leri,A.2004/3/5AgingAnimalsapoptosisBiological MarkersCardiomyopathiesCell AgingCell CountCell Cycle ProteinsCell DeathCell DifferentiationCell DivisionCell LineageCyclin-Dependent Kinase Inhibitor p16Cyclin-Dependent Kinase Inhibitor p21Cyclin-Dependent Kinase Inhibitor p27CyclinscytologyDnaDNA Damagegeneticsheartheart failureHumansInsulin-Like Growth Factor IMalemetabolismMiceMice,TransgenicMultipotent Stem CellsMyocytes,CardiacOxidative StresspathologyPhosphorylationphysiologyProtein Processing,Post-TranslationalProtein-Serine-Threonine KinasesProteinsProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRecombinant Fusion ProteinsRegenerationResearchsurvivalTelomeraseTelomereTumor Suppressor Protein p14ARFTumor Suppressor Protein p53Tumor Suppressor ProteinsultrastructureNot in File514524Circ.Res.944Circ.Res.1169. The roles of apoptosis and senescence in PAH related right heart failure have not been investigated.
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Table e1. Main animal models for research on pulmonary hypertension and right heart failure.ModelSpeciesNotesChronic Hypoxia ADDIN REFMGR.CITE Rabinovitch1981544Age and sex influence on pulmonary hypertension of chronic hypoxia and on recoveryJournal544Age and sex influence on pulmonary hypertension of chronic hypoxia and on recoveryRabinovitch,M.Gamble,W.J.Miettinen,O.S.Reid,L.1981/1AdultAge FactorsAnimalsAnoxiabloodBlood PressureCardiomegalyChronic DiseaseFemaleHemodynamic ProcessesHypertensionHypertension,PulmonaryhypoxiaMalemuscleMuscle,Smooth,VascularOxygenphysiopathologyPulmonary ArteryPulmonary Circulationpulmonary hypertensionRatsSex FactorsNot in FileH62H72Am.J.Physiol.2401Am.J.Physiol.1Partovian1998526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionJournal526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionPartovian,C.Adnot,S.Eddahibi,S.Teiger,E.Levame,M.Dreyfus,P.Raffestin,B.Frelin,C.1998/12analysisAnimalsAnoxiaCapillarieschemically inducedChronic DiseasecomplicationsEndothelial Growth FactorsetiologygeneticsheartHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyhypoxiaLungLymphokinesMalemetabolismmodelmonocrotalineMyocardiumOrgan SizepathologyPerfusionphysiologyphysiopathologypulmonary hypertensionRatsRats,Wistarremodelingright ventricleRNA,MessengerVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVEGFNot in FileH1948H1956Am.J.Physiol.2756 Pt 2Am.J.Physiol.1Fagan2004251Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinaseJournal251Attenuation of acute hypoxic pulmonary vasoconstriction and hypoxic pulmonary hypertension in mice by inhibition of Rho-kinaseFagan,Karen A.Oka,MasahikoBauer,Natalie R.Gebb,Sarah A.Ivy,D.DunbarMorris,Kenneth G.McMurtry,Ivan F.2004/10/1hypoxiahypoxic pulmonary vasoconstrictionnitric oxidepulmonary hypertensionRhoNot in FileL656L664Am J Physiol Lung Cell Mol Physiol2874http://ajplung.physiology.org/cgi/content/abstract/287/4/L656AJP - Lung Cellular and Molecular PhysiologyAm J Physiol Lung Cell Mol Physiol1Abe2006730Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in miceJournal730Long-term inhibition of Rho-kinase ameliorates hypoxia-induced pulmonary hypertension in miceAbe,K.Tawara,S.Oi,K.Hizume,T.Uwatoku,T.Fukumoto,Y.Kaibuchi,K.Shimokawa,H.2006/12ArteriosclerosiseNOSetiologyfasudilHypertensionhypertrophyMicemodelmuscleMuscle Cellsnitric oxideNitric Oxide SynthaseNOPhosphorylationpulmonary hypertensionRatsResearchRhoNot in File280285J Cardiovasc Pharmacol486Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, JapanPM:17204906J Cardiovasc Pharmacol11-4
Rodents and larger animals
Effects of hypoxia mixed with those of increased afterload due to hypoxic pulmonary vascular constrictionMonocrotaline ADDIN REFMGR.CITE Partovian1998526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionJournal526Heart and lung VEGF mRNA expression in rats with monocrotaline- or hypoxia-induced pulmonary hypertensionPartovian,C.Adnot,S.Eddahibi,S.Teiger,E.Levame,M.Dreyfus,P.Raffestin,B.Frelin,C.1998/12analysisAnimalsAnoxiaCapillarieschemically inducedChronic DiseasecomplicationsEndothelial Growth FactorsetiologygeneticsheartHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyhypoxiaLungLymphokinesMalemetabolismmodelmonocrotalineMyocardiumOrgan SizepathologyPerfusionphysiologyphysiopathologypulmonary hypertensionRatsRats,Wistarremodelingright ventricleRNA,MessengerVascular Endothelial Growth Factor AVascular Endothelial Growth FactorsVEGFNot in FileH1948H1956Am.J.Physiol.2756 Pt 2Am.J.Physiol.1Werchan1989642Right ventricular performance after monocrotaline-induced pulmonary hypertensionJournal642Right ventricular performance after monocrotaline-induced pulmonary hypertensionWerchan,P.M.Summer,W.R.Gerdes,A.M.McDonough,K.H.1989/5AnimalsBlood Pressurecardiac outputCardiomegalychemically inducedetiologyheartHeart VentriclesHypertensionHypertension,PulmonaryhypertrophyMalemonocrotalineMyocardiumNOOrgan SizepathologyphysiologyphysiopathologyPressurepulmonary hypertensionPyrrolizidine AlkaloidsRatsRats,Inbred Strainsright ventricleVentricular FunctionNot in FileH1328H1336Am.J Physiol.2565 Pt 2Am.J Physiol.1Farhat1993543Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in ratsJournal543Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in ratsFarhat,M.Y.Chen,M.F.Bhatti,T.Iqbal,A.Cathapermal,S.Ramwell,P.W.1993/10AnimalsBehavior,AnimalBody Weightchemically induceddrug effectsDrug ImplantsEstradiolHemodynamic ProcessesHypertensionHypertension,PulmonaryhypertrophyHypertrophy,Right VentricularLungMacrophagesMalemonocrotalineMyocardiumNOOrgan SizepathologypharmacologyphysiologyphysiopathologyPulmonary ArteryPulmonary Circulationpulmonary edemapulmonary hypertensionRatsRats,Sprague-Dawleyright ventricleNot in File719723Br.J.Pharmacol.1102Br.J.Pharmacol.1Abe2004244Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in RatsJournal244Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in RatsAbe,KohtaroShimokawa,HiroakiMorikawa,KeikoUwatoku,ToyokazuOi,KeijiMatsumoto,YasuharuHattori,TsuyoshiNakashima,YutakaKaibuchi,KozoSueishi,KatsuoTakeshit,Akira2004/2/20apoptosispulmonary hypertensionRhomonocrotalineNot in File385393Circ Res943http://circres.ahajournals.org/cgi/content/abstract/94/3/385Circ Res1Monnet2005643Animal models of heart failure: what is new?Journal643Animal models of heart failure: what is new?Monnet,E.Chachques,J.C.2005/4AnimalsBlood PressureCardiac VolumeCardiomyopathy,DilatedclinicalcomplicationsDisease Models,AnimalDoxorubicinetiologyheartheart failureHeart Failure,CongestiveHeart TransplantationHumansImipramineLigationmodelmonocrotalinemortalityMyocardial IschemiapathologysurgerysurvivaltherapytoxicitytransplantationNot in File14451453Ann.Thorac.Surg.794Ann.Thorac.Surg.1Schermuly2005242Reversal of experimental pulmonary hypertension by PDGF inhibitionJournal242Reversal of experimental pulmonary hypertension by PDGF inhibitionSchermuly,Ralph TheoDony,EvaGhofrani,Hossein ArdeschirPullamsetti,SoniSavai,RajkumarRoth,MarkusSydykov,AkylbekLai,Ying JuWeissmann,NorbertSeeger,WernerGrimminger,Friedrich2005/10/1imatinibPDGFpulmonary hypertensionNot in File28112821J.Clin.Invest.11510http://www.jci.org/cgi/content/abstract/115/10/2811Journal of Clinical InvestigationJ.Clin.Invest.1Kajiya2007580Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive ratsJournal580Impaired NO-mediated vasodilation with increased superoxide but robust EDHF function in right ventricular arterial microvessels of pulmonary hypertensive ratsKajiya,M.Hirota,M.Inai,Y.Kiyooka,T.Morimoto,T.Iwasaki,T.Endo,K.Mohri,S.Shimizu,J.Yada,T.Ogasawara,Y.Naruse,K.Ohe,T.Kajiya,F.2007/1/12Cardiovascular Physiologyheartheart failureHomeostasisHypertensionhypertrophyMalemonocrotalinenitric oxideNOphysiologypulmonary hypertensionRatsStressVasodilationNot in File2737-2744Am.J.Physiol Heart Circ.Physiol.2926Am.J.Physiol Heart Circ.Physiol.1van Albada2006649Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertensionJournal649Prostacyclin therapy increases right ventricular capillarisation in a model for flow-associated pulmonary hypertensionvan Albada,M.E.Berger,R.M.Niggebrugge,M.van,Veghel R.Cromme-Dijkhuis,A.H.Schoemaker,R.G.2006/11/7AnimalsArachidonic AcidAspirinBlood Pressureblood supplyCapillariesCardiologycongenitalcontractilityDisease Models,Animaldrug effectsdrug therapyechocardiographyGene ExpressiongeneticsheartHeart VentriclesHypertensionHypertension,PulmonaryhypertrophyiloprostLungMalemetabolismmodelmonocrotalinemortalityMyocardiumOrgan SizepathologyphysiopathologyPlatelet Aggregation InhibitorsPressureprostacyclinPulmonary ArteryPulmonary Circulationpulmonary hypertensionRatsRats,WistarReceptors,Vascular Endothelial Growth FactorremodelingshuntSurvival Ratetherapeutic usetherapyVascular Endothelial Growth Factor AVentricular RemodelingNot in File107116Eur.J Pharmacol.5491-3Eur.J Pharmacol.1Merklinger2005628Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertensionJournal628Epidermal growth factor receptor blockade mediates smooth muscle cell apoptosis and improves survival in rats with pulmonary hypertensionMerklinger,S.L.Jones,P.L.Martinez,E.C.Rabinovitch,M.2005/7Animalsantagonists & inhibitorsapoptosisclinicalcytologydrug effectsdrug therapyEnzyme InhibitorsHypertensionHypertension,PulmonaryhypertrophyIntegrin alphaVbeta3MaleMetalloproteasesmethodsmonocrotalinemortalitymuscleMuscle,Smooth,VascularMyocytes,Smooth MuscleNOOrgan Culture TechniquesPAHpharmacologyphysiologyPressureProtease InhibitorsPulmonary Arterypulmonary hypertensionRatsRats,Sprague-DawleyReceptor,Epidermal Growth Factorsurvivaltherapeutic usetherapyTyrosineTyrphostinsNot in File423431Circulation.1123Circulation.1Kimura2007742Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac HypertrophyJournal742Cardiac Sympathetic Rejuvenation: A Link Between Nerve Function and Cardiac HypertrophyKimura,KensukeIeda,MasakiKanazawa,HideakiYagi,TakashiTsunoda,MakotoNinomiya,Shin ichiKurosawa,HiroyukiYoshimi,KenjiMochizuki,HidekiYamazaki,KazutoOgawa,SatoshiFukuda,Keiichi2007/6/22Angiotensin IIendothelin-1hearthypertrophyinnervationmonocrotalineNorepinephrinepulmonary hypertensionRatsright ventricleNot in File17551764Circ Res10012http://circres.ahajournals.org/cgi/content/abstract/100/12/1755Circ Res1Akhavein2007748Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult ratsJournal748Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult ratsAkhavein,F.-Michel,E.JeanSeifert,E.Rohlicek,C.V.2007/7/1monocrotalineMyocarditispulmonary hypertensionRatsVentricular FunctionNot in File287295J Appl Physiol1031http://jap.physiology.org/cgi/content/abstract/103/1/287Journal of Applied PhysiologyJ Appl Physiol12;5-12;14;15RatPossible systemic activation of pro-inflammatory and pro-coagulant pathways contributing to heart failureSU5416/Hypoxia ADDIN REFMGR.CITE Taraseviciene-Stewart2001264Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertensionJournal264Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertensionTaraseviciene-Stewart,L.kasahara,YasunoriAlger,LoriHirth,PeterMcMahon,GeraldWaltenberger,JohannesVoelkel,Norbert F.Tuder,Rubin M.2001/2/1hypoxiapulmonary hypertensionVEGFapoptosisNot in File427438FASEB J.152http://www.fasebj.org/cgi/content/abstract/15/2/427The FASEB JournalFASEB J.1Oka2007735Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in ratsJournal735Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in ratsOka,M.Homma,N.Taraseviciene-Stewart,L.Morris,K.G.Kraskauskas,D.Burns,N.Voelkel,N.F.McMurtry,I.F.2007/3/301-(5-Isoquinolinesulfonyl)-2-MethylpiperazineAdultanalogs & derivativesAnimalsAnoxiaantagonists & inhibitorschemically inducedDisease Models,AnimalDisease Progressiondrug effectsenzymologyfasudilHypertensionHypertension,PulmonaryhypoxiailoprostIndolesIntracellular Signaling Peptides and ProteinsLungMalemetabolismmodelMyosin-Light-Chain PhosphataseNOOrgan Culture TechniquesPAHPeptides,CyclicpharmacologyPhosphorylationphysiopathologyPressureProtein-Serine-Threonine KinasesPulmonary Arterypulmonary hypertensionPyrrolesRatsRats,Sprague-DawleyReceptor,Endothelin AremodelingResearchRhoVascular Endothelial Growth Factor Receptor-2Vascular ResistanceVasoconstrictionVasodilator AgentsNot in File923929Circ.Res.1006Circ.Res.1Taraseviciene-Stewart2006209Simvastatin Causes Endothelial Cell Apoptosis and Attenuates Severe Pulmonary HypertensionJournal209Simvastatin Causes Endothelial Cell Apoptosis and Attenuates Severe Pulmonary HypertensionTaraseviciene-Stewart,LaimuteScerbavicius,RobertasChoe,Kang HyeonCool,CarlyneWood,KathyTuder,Rubin M.Burns,NanaKasper,MichaelVoelkel,Norbert F.2006/5/12apoptosisendotheliumpulmonary hypertensionstatinNot in File00491Am J Physiol Lung Cell Mol Physiolhttp://ajplung.physiology.org/cgi/content/abstract/00491.2005v1AJP - Lung Cellular and Molecular PhysiologyAm J Physiol Lung Cell Mol Physiol116-18Rateffects of VEGF receptor blockade on myocardial microcirculation are unknown
Pulmonary artery banding ADDIN REFMGR.CITE Thompson1998639Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overloadJournal639Upregulation of the cardiac homeobox gene Nkx2-5 (CSX) in feline right ventricular pressure overloadThompson,J.T.Rackley,M.S.O'Brien,T.X.1998/5AdultAnimalsAtrial Natriuretic FactorBlood PressureCatsDnageneticsheartHomeodomain ProteinshypertrophyHypertrophy,Right VentricularmodelpathologyphysiopathologyPressurePulmonary ArteryResearchRnaTranscription FactorsUp-RegulationVentricular PressureNot in FileH1569H1573Am.J Physiol.2745 Pt 2Am.J Physiol.1Orito2004640Time course sequences of angiotensin converting enzyme and chymase-like activities during development of right ventricular hypertrophy induced by pulmonary artery constriction in dogsJournal640Time course sequences of angiotensin converting enzyme and chymase-like activities during development of right ventricular hypertrophy induced by pulmonary artery constriction in dogsOrito,K.Yamane,T.Kanai,T.Fujii,Y.Wakao,Y.Matsuda,H.2004/7/16AnimalsbloodBlood Flow VelocityChymasesConstrictionConstriction,PathologicDisease Models,AnimalDogsechocardiographyenzymologyfibrosisheartHeart VentriclesHistological TechniqueshypertrophyHypertrophy,Right VentricularmetabolismpathologyPeptidyl-Dipeptidase ApharmacologyphysiologyphysiopathologyPressurePulmonary ArteryradiographyReninright ventricleSerine EndopeptidasesTime FactorsVentricular PressureNot in File11351145Life Sci.759Life Sci.1Kerbaul2007561How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertensionJournal561How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertensionKerbaul,F.Brimioulle,S.Rondelet,B.Dewachter,C.Hubloue,I.Naeije,R.2007/4/15cardiac outputcontractilityDogsepoprostenolheartheart failureHypertensionmethodsmodelphysiologyprostacyclinpulmonary hypertensionright ventricletherapyVascular ResistanceNot in File846850Am.J.Respir.Crit Care Med.1758Am.J.Respir.Crit Care Med.1Saito1991578Oxygen metabolism of the hypertrophic right ventricle in open chest dogsJournal578Oxygen metabolism of the hypertrophic right ventricle in open chest dogsSaito,D.Tani,H.Kusachi,S.Uchida,S.Ohbayashi,N.Marutani,M.Maekawa,K.Tsuji,T.Haraoka,S.1991/9AnimalsbloodCardiomegalyCoronary VesselsDisease Models,AnimalDogsdrug effectsFemalehypertrophyIsoproterenolMalemetabolismMyocardiumNOOxygenOxygen Consumptionoxygen extractionpharmacologyphysiologyPulmonary ArteryRegional Blood Flowright ventricleSodiumVentricular PressureNot in File731739Cardiovasc.Res.259Cardiovasc.Res.1Adachi1995648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingJournal648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingAdachi,S.Ito,H.Ohta,Y.Tanaka,M.Ishiyama,S.Nagata,M.Toyozaki,T.Hirata,Y.Marumo,F.Hiroe,M.1995/1ActinsanalysisAnimalsAtrial Natriuretic Factorbiosynthesisbrain natriuretic peptideGene ExpressionHeart VentricleshypertrophyHypertrophy,Right VentricularIn Situ HybridizationMalemetabolismmodelMyocardiumNatriuretic Peptide,BrainNatriuretic PeptidesNerve Tissue ProteinsOrgan SpecificityPeptidesphysiologyphysiopathologyPressureProbabilityPulmonary ArteryRatsRats,Wistarright ventricleRNA,MessengerStressSystoleVentricular PressureNot in FileH162H169Am.J Physiol.2681 Pt 2Am.J Physiol.1Bishop1994645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadJournal645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadBishop,J.E.Rhodes,S.Laurent,G.J.Low,R.B.Stirewalt,W.S.1994/10analysisAnimalsbiosynthesisBlotting,NorthernCollagenGene ExpressiongeneticsheartHeart VentricleshypertrophyHypertrophy,Right VentricularLungMalemetabolismmethodsPressureProcollagenPulmonary ArteryRabbitsright ventricleRNA,MessengerNot in File15811585Cardiovasc.Res.2810Cardiovasc.Res.1Matsui1995637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitJournal637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitMatsui,H.MacLennan,D.H.Alpert,N.R.Periasamy,M.1995/1ActinsAnimalsCalcium ChannelsCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCardiomegalycomplicationsdiastolic functionetiologyGene ExpressiongeneticsheartHypertensionhypertrophyMalemetabolismmuscleMuscle ProteinsMyocardiumphysiologyPressureProteinsPulmonary ArteryRabbitsRNA,MessengerRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumNot in FileC252C258Am.J Physiol.2681 Pt 1Am.J Physiol.1LekanneDeprez1998641Changing patterns of gene expression in the pulmonary trunk-banded rat heartJournal641Changing patterns of gene expression in the pulmonary trunk-banded rat heartLekanneDeprez,R.H.van den Hoff,M.J.de Boer,P.A.Ruijter,P.M.Maas,A.A.Chamuleau,R.A.Lamers,W.H.Moorman,A.F.1998/9AmmoniaAnimalsAtrial Natriuretic FactorBiological MarkersbiosynthesisbloodBlotting,NortherncalciumCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCollagenConstrictionCoronary CirculationdiagnosisfibrosisGene Expressiongeneticsheartheart failureHeart Failure,CongestivehypertrophyIn Situ HybridizationLiverMalemetabolismmodelMyocardiumPulmonary ArteryPulmonary CirculationRatsRats,Wistarright ventricleRNA,MessengerStresssurgeryNot in File18771888J Mol.Cell Cardiol.309J Mol.Cell Cardiol.1Ikeda1999647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingJournal647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingIkeda,S.Hamada,M.Hiwada,K.1999analysisAnimalsapoptosisbcl-2-Associated X ProteinBody WeightConstrictioncytologyDNA FragmentationGenes,p53geneticsHeart VentriclesHypertrophy,Right VentricularImmunohistochemistryIn Situ Nick-End LabelingMalemetabolismMyocardiumphysiologyPressureProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRatsRats,Sprague-Dawleyright ventricleRNA,MessengersurgeryTime FactorsTumor Suppressor Protein p53Up-RegulationVentricular PressureNot in File925933Life Sci.659Life Sci.1Rouleau2001636Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathwayJournal636Cardioprotective effects of ramipril and losartan in right ventricular pressure overload in the rabbit: importance of kinins and influence on angiotensin II type 1 receptor signaling pathwayRouleau,J.L.Kapuku,G.Pelletier,S.Gosselin,H.Adam,A.Gagnon,C.Lambert,C.Meloche,S.2001/8/21Angiotensin IIAngiotensin-Converting Enzyme InhibitorsAnimalsantagonists & inhibitorscontractilityDisease Models,AnimalDose-Response Relationship,Drugdrug effectsdrug therapyElectric StimulationGTP-Binding ProteinsheartHemodynamic ProcesseshypertrophyKininsLosartanMalemetabolismmethodsmodelmuscleMyocardial ContractionMyocardiumNOOrgan SizePapillary MusclespathologypharmacologyPhenylephrinephysiopathologyPressureProtein SubunitsPulmonary ArteryRabbitsRamiprilReceptor,Angiotensin,Type 1Receptor,Angiotensin,Type 2Receptors,BradykininReceptors,Angiotensinright ventricleSignal TransductionVentricular Dysfunction,RightVentricular PressureNot in File939944Circulation.1048Circulation.1Emani2001638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingJournal638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingEmani,S.M.Shah,A.S.White,D.C.Glower,D.D.Koch,W.J.2001/11Animalsbeta-Adrenergic Receptor Kinasebeta-GalactosidaseCarrier ProteinsclinicalGene Therapygene transferHeart VentricleshypertrophymethodsmortalitypathologyPeptidesPressurePulmonary ArteryRabbitsRecombinant ProteinssurgerysurvivalSurvival Ratetherapeutic usetherapyTransgenesVentricular Dysfunction,RightVentricular PressureNot in File16571661Ann.Thorac.Surg.725Ann.Thorac.Surg.1Bar2003644Upregulation of embryonic transcription factors in right ventricular hypertrophyJournal644Upregulation of embryonic transcription factors in right ventricular hypertrophyBar,H.Kreuzer,J.Cojoc,A.Jahn,L.2003/9AdultAnimalsAtrial Natriuretic FactorBasic Helix-Loop-Helix Transcription FactorsBinding SitesBiological MarkersBlotting,WesternCardiologyDisease Models,AnimalDNA-Binding ProteinsGATA4 Transcription FactorGene ExpressionheartHumanshypertrophyHypertrophy,Right VentricularImmunohistochemistryLigationMalemetabolismMicroscopy,FluorescencemodelMyocardiumMyogenic Regulatory FactorsPressureProteinsPulmonary ArteryRatsRats,Sprague-Dawleyright ventricleTranscription FactorsUp-RegulationZebrafish ProteinsNot in File285294Basic Res.Cardiol.985Basic Res.Cardiol.1Braun2003646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesJournal646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesBraun,M.U.Szalai,P.Strasser,R.H.Borst,M.M.2003/9/1analogs & derivativesanalysisAngiotensin-Converting Enzyme InhibitorsAnimalsapoptosisbcl-2-Associated X ProteinCalcineurinCardiologyCaspase 3chemistryConstriction,PathologicCytosoldrug therapyenzymologyhypertrophyHypertrophy,Right VentricularImmunoblottingIsoenzymesMalemetabolismmethodsMyocardiumNOpathologypharmacologyPressureProtein Kinase CProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRamiprilRatsRats,WistarremodelingRenin-Angiotensin SystemNot in File658667Cardiovasc.Res.593Cardiovasc.Res.119-31Rat, Rabbit, Dog, CatHigh mortality rates in rodents, only suitable to study chronic pressure overload with moderate constriction
re-expression of fetal genes (e.g. ANP, GATA-4 MEF2C) ADDIN REFMGR.CITE Adachi1995648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingJournal648Distribution of mRNAs for natriuretic peptides in RV hypertrophy after pulmonary arterial bandingAdachi,S.Ito,H.Ohta,Y.Tanaka,M.Ishiyama,S.Nagata,M.Toyozaki,T.Hirata,Y.Marumo,F.Hiroe,M.1995/1ActinsanalysisAnimalsAtrial Natriuretic Factorbiosynthesisbrain natriuretic peptideGene ExpressionHeart VentricleshypertrophyHypertrophy,Right VentricularIn Situ HybridizationMalemetabolismmodelMyocardiumNatriuretic Peptide,BrainNatriuretic PeptidesNerve Tissue ProteinsOrgan SpecificityPeptidesphysiologyphysiopathologyPressureProbabilityPulmonary ArteryRatsRats,Wistarright ventricleRNA,MessengerStressSystoleVentricular PressureNot in FileH162H169Am.J Physiol.2681 Pt 2Am.J Physiol.1Bar2003644Upregulation of embryonic transcription factors in right ventricular hypertrophyJournal644Upregulation of embryonic transcription factors in right ventricular hypertrophyBar,H.Kreuzer,J.Cojoc,A.Jahn,L.2003/9AdultAnimalsAtrial Natriuretic FactorBasic Helix-Loop-Helix Transcription FactorsBinding SitesBiological MarkersBlotting,WesternCardiologyDisease Models,AnimalDNA-Binding ProteinsGATA4 Transcription FactorGene ExpressionheartHumanshypertrophyHypertrophy,Right VentricularImmunohistochemistryLigationMalemetabolismMicroscopy,FluorescencemodelMyocardiumMyogenic Regulatory FactorsPressureProteinsPulmonary ArteryRatsRats,Sprague-Dawleyright ventricleTranscription FactorsUp-RegulationZebrafish ProteinsNot in File285294Basic Res.Cardiol. < V o l u m e > 9 8 < / V o l u m e > < I s s u e > 5 < / I s s u e > < Z Z _ J o u r n a l S t d A b b r e v > < f n a m e = " S y s t e m " > B a s i c R e s . C a r d i o l . < / f > < / Z Z _ J o u r n a l S t d A b b r e v > < Z Z _ W o r k f o r m I D > 1 < / Z Z _ W o r k f o r m I D > < / M D L > < / C i t e > < / R e f m a n > 2 3 ; 3 0 , - A R d y s r e g u l a t i o n A D D I N R E F M G R . C I T E < R e f m a n > < C i t e > < A u t h o r > E m a n i < / A u t h o r>2001638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingJournal638Right ventricular gene therapy with a beta-adrenergic receptor kinase inhibitor improves survival after pulmonary artery bandingEmani,S.M.Shah,A.S.White,D.C.Glower,D.D.Koch,W.J.2001/11Animalsbeta-Adrenergic Receptor Kinasebeta-GalactosidaseCarrier ProteinsclinicalGene Therapygene transferHeart VentricleshypertrophymethodsmortalitypathologyPeptidesPressurePulmonary ArteryRabbitsRecombinant ProteinssurgerysurvivalSurvival Ratetherapeutic usetherapyTransgenesVentricular Dysfunction,RightVentricular PressureNot in File16571661Ann.Thorac.Surg.725Ann.Thorac.Surg.129, altered expression of SR proteins ADDIN REFMGR.CITE Matsui1995637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitJournal637Sarcoplasmic reticulum gene expression in pressure overload-induced cardiac hypertrophy in rabbitMatsui,H.MacLennan,D.H.Alpert,N.R.Periasamy,M.1995/1ActinsAnimalsCalcium ChannelsCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCardiomegalycomplicationsdiastolic functionetiologyGene ExpressiongeneticsheartHypertensionhypertrophyMalemetabolismmuscleMuscle ProteinsMyocardiumphysiologyPressureProteinsPulmonary ArteryRabbitsRNA,MessengerRyanodine Receptor Calcium Release ChannelSarcoplasmic ReticulumNot in FileC252C258Am.J Physiol.2681 Pt 1Am.J Physiol.1LekanneDeprez1998641Changing patterns of gene expression in the pulmonary trunk-banded rat heartJournal641Changing patterns of gene expression in the pulmonary trunk-banded rat heartLekanneDeprez,R.H.van den Hoff,M.J.de Boer,P.A.Ruijter,P.M.Maas,A.A.Chamuleau,R.A.Lamers,W.H.Moorman,A.F.1998/9AmmoniaAnimalsAtrial Natriuretic FactorBiological MarkersbiosynthesisbloodBlotting,NortherncalciumCalcium-Binding ProteinsCalcium-Transporting ATPasesCalsequestrinCollagenConstrictionCoronary CirculationdiagnosisfibrosisGene Expressiongeneticsheartheart failureHeart Failure,CongestivehypertrophyIn Situ HybridizationLiverMalemetabolismmodelMyocardiumPulmonary ArteryPulmonary CirculationRatsRats,Wistarright ventricleRNA,MessengerStresssurgeryNot in File18771888J Mol.Cell Cardiol.309J Mol.Cell Cardiol.125;26, increased apoptosis ADDIN REFMGR.CITE Ikeda1999647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingJournal647Cardiomyocyte apoptosis with enhanced expression of P53 and Bax in right ventricle after pulmonary arterial bandingIkeda,S.Hamada,M.Hiwada,K.1999analysisAnimalsapoptosisbcl-2-Associated X ProteinBody WeightConstrictioncytologyDNA FragmentationGenes,p53geneticsHeart VentriclesHypertrophy,Right VentricularImmunohistochemistryIn Situ Nick-End LabelingMalemetabolismMyocardiumphysiologyPressureProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRatsRats,Sprague-Dawleyright ventricleRNA,MessengersurgeryTime FactorsTumor Suppressor Protein p53Up-RegulationVentricular PressureNot in File925933Life Sci.659Life Sci.1Braun2003646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesJournal646Right ventricular hypertrophy and apoptosis after pulmonary artery banding: regulation of PKC isozymesBraun,M.U.Szalai,P.Strasser,R.H.Borst,M.M.2003/9/1analogs & derivativesanalysisAngiotensin-Converting Enzyme InhibitorsAnimalsapoptosisbcl-2-Associated X ProteinCalcineurinCardiologyCaspase 3chemistryConstriction,PathologicCytosoldrug therapyenzymologyhypertrophyHypertrophy,Right VentricularImmunoblottingIsoenzymesMalemetabolismmethodsMyocardiumNOpathologypharmacologyPressureProtein Kinase CProto-Oncogene ProteinsProto-Oncogene Proteins c-bcl-2Pulmonary ArteryRamiprilRatsRats,WistarremodelingRenin-Angiotensin SystemNot in File658667Cardiovasc.Res.593Cardiovasc.Res.127;31, myocardial fibrosis ADDIN REFMGR.CITE Bishop1994645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadJournal645Increased collagen synthesis and decreased collagen degradation in right ventricular hypertrophy induced by pressure overloadBishop,J.E.Rhodes,S.Laurent,G.J.Low,R.B.Stirewalt,W.S.1994/10analysisAnimalsbiosynthesisBlotting,NorthernCollagenGene ExpressiongeneticsheartHeart VentricleshypertrophyHypertrophy,Right VentricularLungMalemetabolismmethodsPressureProcollagenPulmonary ArteryRabbitsright ventricleRNA,MessengerNot in File15811585Cardiovasc.Res.2810Cardiovasc.Res.124 as in left ventricular overload
no studies on the relative importance of different signaling pathways in the transition from hypertrophy to failureVEGF = vascular endothelial growth factor; ANP = a t r i a l n a t r i u r e t i c p e p t i d e ; - A R = - a d r e n e r g i c r e c e p t o r . T a b l e e 2 . I m p o r t a n t a n i m a l m o d e l s f o r r e s e a r c h o n l e f t h e a r t f a i l u r e , w i t h r e l e v a n c e t o t h e s t u d y o f r i g h t h e a r t f a i l u r e i n p u l m o n a r y h y p e r t e n s i o n .
M o d e l S p e c i e s N o t e s T A C A D D I N R E F M G R . C I T E < R e f man>Hirota1999415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressJournal415Loss of a gp130 cardiac muscle cell survival pathway is a critical event in the onset of heart failure during biomechanical stressHirota,H.Chen,J.Betz,U.A.Rajewsky,K.Gu,Y.Ross,J.,Jr.Muller,W.Chien,K.R.1999/4/16AnimalsAntigens,CDapoptosisBiomechanicsCardiomegalyCardiomyopathiesCell SurvivalCytokine Receptor gp130CytokinesembryologyetiologyFetal HeartGene Expression Regulation,Developmentalgeneticsgp130heartheart failureHeart Failure,CongestivehypertrophyMembrane GlycoproteinsMiceMice,KnockoutmuscleMyocardiumpathologyphysiologyphysiopathologyReceptors,CytokinesurvivalNot in File189198Cell.972Cell.1Tamura2000474Cardiac fibrosis in mice lacking brain natriuretic peptideJournal474Cardiac fibrosis in mice lacking brain natriuretic peptideTamura,N.Ogawa,Y.Chusho,H.Nakamura,K.Nakao,K.Suda,M.Kasahara,M.Hashimoto,R.Katsuura,G.Mukoyama,M.Itoh,H.Saito,Y.Tanaka,I.Otani,H.Katsuki,M.2000/4/11AnimalsBase SequencebiosynthesisBlood Pressurebrain natriuretic peptideclinicalExtracellular MatrixfibroblastFibroblastsfibrosisgeneticsheartheart failureHypertensionhypertrophyMiceMice,KnockoutMicroscopy,ElectronMyocardial InfarctionMyocardiumNatriuretic Peptide,BrainNOOligonucleotides,AntisensepathologyPhenotypephysiologyremodelingRNA,MessengerultrastructureVentricular PressureVentricular RemodelingWater-Electrolyte BalanceNot in File42394244Proc.Natl.Acad.Sci.U.S.A.978Proc.Natl.Acad.Sci.U.S.A.1Bueno2001597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoJournal597The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivoBueno,O.F.De Windt,L.J.Lim,H.W.Tymitz,K.M.Witt,S.A.Kimball,T.R.Molkentin,J.D.2001/1AdenoviridaeAnimalsAnimals,NewbornAtrial Natriuretic FactorBlotting,WesternCa(2+)-Calmodulin Dependent Protein KinaseCardiomegalyCatecholaminesCells,Culturedchemically inducedcytologyDNA,Recombinantdrug effectsendothelin-1enzymologyFemaleGene Expressiongene transferGene Transfer TechniquesGenetic VectorsgeneticshearthypertrophymetabolismMiceMice,TransgenicMyocardiumNOpharmacologyPhenylephrinePhosphorylationProtein-Tyrosine-PhosphataseRatsRNA,MessengerStressNot in File8896Circ.Res.881Circ.Res.1Takemoto2001430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyJournal430Statins as antioxidant therapy for preventing cardiac myocyte hypertrophyTakemoto,M.Node,K.Nakagami,H.Liao,Y.Grimm,M.Takemoto,Y.Kitakaze,M.Liao,J.K.2001/11Angiotensin IIAnimalsAntioxidantsAtrial Natriuretic FactorCardiomegalyCells,Cultureddrug effectsgeneticshearthypertrophyLeucinemetabolismMicemortalityMyocardiumNOOxidation-Reductionpharmacologyphysiologyprevention & controlPromoter Regions (Genetics)rac1 GTP-Binding ProteinRatsRats,Sprague-DawleyRhosimvastatinstatinSuperoxidestherapyNot in File14291437J.Clin.Invest.10810Journal of Clinical InvestigationJ.Clin.Invest.1Asakura2002667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyJournal667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyAsakura,M.Kitakaze,M.Takashima,S.Liao,Y.Ishikura,F.Yoshinaka,T.Ohmoto,H.Node,K.Yoshino,K.Ishiguro,H.Asanuma,H.Sanada,S.Matsumura,Y.Takeda,H.Beppu,S.Tada,M.Hori,M.Higashiyama,S.2002/1ADAM Proteinsanalogs & derivativesAngiotensin IIAnimalsantagonists & inhibitorsAorta,ThoracicCardiomegalyDisease Models,AnimalDisintegrinsdrug effectsdrug therapyEpidermal Growth FactorgeneticsGlycineGPCRGTP-Binding ProteinsheartHeart VentriclesHydroxamic AcidsHypertensionhypertrophyMaleMembrane ProteinsmetabolismMetalloendopeptidasesMicepharmacologyPhenylephrineProtease InhibitorsProtein Processing,Post-TranslationalRatsReceptor,Epidermal Growth FactorSignal TransductionsurgerySystoletherapeutic usetherapyTrans-Activation (Genetics)Not in File3540Nat.Med.81Nat.Med.1Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.1Hill2002596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionJournal596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionHill,J.A.Rothermel,B.Yoo,K.D.Cabuay,B.Demetroulis,E.Weiss,R.M.Kutschke,W.Bassel-Duby,R.Williams,R.S.2002/3/22Animalsantagonists & inhibitorsAortaBlood PressureBlotting,NorthernCalcineurinDNA,ComplementaryDose-Response Relationship,DrugechocardiographyElectroencephalographyheartHeart DiseasesHumanshypertrophyMalemetabolismMiceMice,TransgenicMyocardiumpathologyPressureProtein BindingProtein IsoformsRnaRNA,MessengerStressTime FactorsUp-RegulationNot in File1025110255J.Biol.Chem.27712Journal of Biological ChemistryJ.Biol.Chem.1Hara2005563Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptorJournal563Augmented cardiac hypertrophy in response to pressure overload in mice lacking the prostaglandin I2 receptorHara,A.Yuhki,K.Fujino,T.Yamada,T.Takayama,K.Kuriyama,S.Takahata,O.Karibe,H.Okada,Y.Xiao,C.Y.Ma,H.Narumiya,S.Ushikubi,F.2005/7/5analogs & derivativesanalysisAnimalsAortaBiological MarkersbloodCardiomegalyCell EnlargementcomplicationsCyclic AMPdeficiencyDisease Models,AnimalepoprostenoletiologyFemalefibrosisgeneticsheartHypertensionhypertrophymethodsMiceMice,KnockoutmodelMyocytes,CardiacNOpathologypharmacologyphysiologyReceptors,EpoprostenolRNA,MessengerNot in File8492Circulation.1121Circulation.1Takimoto2005528Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure loadJournal528Oxidant stress from nitric oxide synthase-3 uncoupling stimulates cardiac pathologic remodeling from chronic pressure loadTakimoto,E.Champion,H.C.Li,M.Ren,S.Rodriguez,E.R.Tavazzi,B.Lazzarino,G.Paolocci,N.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/5analogs & derivativesAnimalsBiopterinCardiologyCardiomegalyenzymologyfibrosishearthypertrophyImmunoblottingmetabolismMicenitric oxideNitric Oxide SynthaseNitric Oxide Synthase Type IINitric Oxide Synthase Type IIINOOxidative Stressphysiologyreactive oxygen speciesremodelingStressVentricular Dysfunction,LeftNot in File12211231J.Clin.Invest.1155Journal of Clinical InvestigationJ.Clin.Invest.1Perrino2006470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionJournal470Intermittent pressure overload triggers hypertrophy-independent cardiac dysfunction and vascular rarefactionPerrino,C.Naga Prasad,S.V.Mao,L.Noma,T.Yan,Z.Kim,H.S.Smithies,O.Rockman,H.A.2006/61-Phosphatidylinositol 3-KinaseAdrenergic beta-AntagonistsAnimalsantagonists & inhibitorsbeta-Adrenergic Receptor KinaseBlood PressureBlood VesselsCardiac Output,LowCardiomegalyCells,CulturedcytologyechocardiographyexerciseFemaleGene ExpressionGene Expression RegulationgeneticsheartHemodynamic ProcessesHumansHypertensionhypertrophyHypertrophy,Left VentricularmetabolismMetoprololMiceMice,Inbred C57BLMice,TransgenicMyocardiumpathologyPhenotypephysiologyphysiopathologyReceptors,Adrenergic,betaSignal TransductionStressNot in File15471560J.Clin.Invest.1166Journal of Clinical InvestigationJ.Clin.Invest.1Zhang2006287Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosisJournal287Targeted deletion of ROCK1 protects the heart against pressure overload by inhibiting reactive fibrosisZhang,Ying MinBo,JacquelineTaffet,George E.Chang,JiangShi,JianjianReddy,Anilkumar K.Michael,Lloyd H.Schneider,Michael D.Entman,Mark L.Schwartz,Robert J.Wei,Lei2006/5/1myocardial fibrosisheartremodelingRhoNot in File916925FASEB J.207http://www.fasebj.org/cgi/content/abstract/20/7/916The FASEB JournalFASEB J.1Izumiya2006566Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overloadJournal566Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overloadIzumiya,Y.Shiojima,I.Sato,K.Sawyer,D.B.Colucci,W.S.Walsh,K.2006/5Adaptation,PhysiologicalAnimalsantagonists & inhibitorsAortaCapillariesCardiac Output,LowCardiomegalyCollagencomplicationsConstrictionCoronary CirculationechocardiographyetiologyfibrosisGene Transfer Techniquesgeneticsheartheart failureHypertensionhypertrophyImmunoglobulin Fc FragmentsMalemetabolismMiceMice,Inbred C57BLmodelMyocardial Contractionmyocardial fibrosisMyocardiumNOpathologyphysiopathologyUp-RegulationVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2VEGFVentricular RemodelingNot in File887893Hypertension.475Hypertension.1Kuwahara2007618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityJournal618Modulation of adverse cardiac remodeling by STARS, a mediator of MEF2 signaling and SRF activityKuwahara,K.Pipes,G.C.McAnally,J.Richardson,J.A.Hill,J.A.Bassel-Duby,R.Olson,E.N.2007/5CalcineurinCardiomyopathiesCytoskeletal ProteinsCytoskeletonhearthypertrophymodelmusclepathologyPressureProteinsremodelingRhoStressNot in File13241334J.Clin.Invest.1175Journal of Clinical InvestigationJ.Clin.Invest.1Ohba2007508Upregulation of TRPC1 in the development of cardiac hypertrophyJournal508Upregulation of TRPC1 in the development of cardiac hypertrophyOhba,T.Watanabe,H.Murakami,M.Takahashi,Y.Iino,K.Kuromitsu,S.Mori,Y.Ono,K.Iijima,T.Ito,H.2007/3Angiotensin IIAtrial Natriuretic Factorbrain natriuretic peptideendothelin-1hearthypertrophyPhenylephrineRatsRnaNot in File498507J.Mol.Cell Cardiol.423J.Mol.Cell Cardiol.1Sano2007523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadJournal523p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overloadSano,M.Minamino,T.Toko,H.Miyauchi,H.Orimo,M.Qin,Y.Akazawa,H.Tateno,K.Kayama,Y.Harada,M.Shimizu,I.Asahara,T.Hamada,H.Tomita,S.Molkentin,J.D.Zou,Y.Komuro,I.2007/3/22Animalsantagonists & inhibitorsAortaBlood PressureCardiac Output,LowCardiomegalyCoronary CirculationDisease Progressiongeneticsheartheart failurehypertrophyHypoxia-Inducible Factor 1,alpha SubunitmetabolismMiceNeovascularization,PathologicpathologyphysiopathologyTumor Suppressor Protein p53Not in File444448Nature.4467134Nature.1Trivedi2007606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityJournal606Hdac2 regulates the cardiac hypertrophic response by modulating Gsk3 beta activityTrivedi,C.M.Luo,Y.Yin,Z.Zhang,M.Zhu,W.Wang,T.Floss,T.Goettlicher,M.Noppinger,P.R.Wurst,W.Ferrari,V.A.Abrams,C.S.Gruber,P.J.Epstein,J.A.2007/3AdultAnimalsbiosynthesisCardiomegalydeficiencyembryologyEnzyme ActivationenzymologyFetusgeneticsGlycogen Synthase Kinase 3heartheart failureHistone DeacetylaseshypertrophyIsoenzymesmetabolismMiceMice,KnockoutMice,TransgenicMolecular Sequence DataphysiologyRepressor ProteinsResearchSignal TransductionStressNot in File324331Nat.Med.133Nat.Med.1Care2007634MicroRNA-133 controls cardiac hypertrophyJournal634MicroRNA-133 controls cardiac hypertrophyCare,A.Catalucci,D.Felicetti,F.Bonci,D.Addario,A.Gallo,P.Bang,M.L.Segnalini,P.Gu,Y.Dalton,N.D.Elia,L.Latronico,M.V.Hoydal,M.Autore,C.Russo,M.A.Dorn,G.W.Ellingsen,O.Ruiz-Lozano,P.Peterson,K.L.Croce,C.M.Peschle,C.Condorelli,G.2007/5hearthypertrophyMicroRNAsmodeloncologySignal TransductionNot in File613618Nat.Med.135Nat.Med.1Van Rooij E.2007635Control of stress-dependent cardiac growth and gene expression by a microRNAJournal635Control of stress-dependent cardiac growth and gene expression by a microRNAVan Rooij E.Sutherland,L.B.Qi,X.Richardson,J.A.Hill,J.Olson,E.N.2007/4/27AnimalsCardiac MyosinsCardiomegalycontractilityDown-RegulationfibrosisGene DeletionGene ExpressionGene Expression RegulationgeneticsheartHeart DiseaseshypertrophyHypothyroidismIntronsmetabolismMiceMice,TransgenicMicroRNAsMyocardial ContractionMyocardiumMyocytes,CardiacMyosin Heavy ChainsOligonucleotide Array Sequence AnalysispathologyphysiologyphysiopathologyProteinsRatsSignal TransductionStressTranscription FactorsTriiodothyronineUp-RegulationVentricular MyosinsNot in File575579Science.3165824Science.1Jiang2007525Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in miceJournal525Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in miceJiang,Y.Reynolds,C.Xiao,C.Feng,W.Zhou,Z.Rodriguez,W.Tyagi,S.C.Eaton,J.W.Saari,J.T.Kang,Y.J.2007/3AnimalsantibodiesCardiomyopathiesCardiomyopathy,HypertrophicCells,CulturedChronic DiseasecomplicationsCopperdiet therapyDietary SupplementsDisease Models,Animaletiologyheartheart failureHIF-1alphaHumansHypertensionhypertrophyMaleMiceMice,Inbred C57BLmodelphysiopathologytherapeutic useVEGFNot in File657666J.Exp.Med.2043The Journal of Experimental MedicineJ.Exp.Med.1Dickey2007609Differential Regulation of Membrane Guanylyl Cyclases in Congestive Heart Failure: NPR-B, Not NPR-A, Is the Predominant Natriuretic Peptide Receptor in the Failing HeartJournal609Differential Regulation of Membrane Guanylyl Cyclases in Congestive Heart Failure: NPR-B, Not NPR-A, Is the Predominant Natriuretic Peptide Receptor in the Failing HeartDickey,D.M.Flora,D.R.Bryan,P.M.Xu,X.Chen,Y.Potter,L.R.2007/4/5bloodBlood PressureCardiologyheartheart failurehypertrophyMicepharmacologyPressureNot in File35183522Endocrinology.1487Endocrinology.1Zahabi2003675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsJournal675Expression of constitutively active guanylate cyclase in cardiomyocytes inhibits the hypertrophic effects of isoproterenol and aortic constriction on mouse heartsZahabi,A.Picard,S.Fortin,N.Reudelhuber,T.L.Deschepper,C.F.2003/11/28Adenylate CyclaseAnimalsAortabiosynthesisBlood PressureBlotting,NorthernchemistryConstrictionCos CellsCyclic GMPDNA,Complementarydrug effectsechocardiographyenzymologyGene ExpressiongeneticsGuanylate CyclaseheartHypertensionhypertrophyIsoproterenolMalemetabolismMiceMice,Inbred C3HMice,Inbred C57BLMice,KnockoutMice,TransgenicmodelMyocardiumNOpathologyPeptidespharmacologyProtein Structure,TertiaryRatsReceptors,Atrial Natriuretic FactorremodelingResearchRNA,MessengerTissue DistributionTransfectionTransgenesNot in File4769447699J Biol.Chem.27848J Biol.Chem.1Takimoto2005677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyJournal677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyTakimoto,E.Champion,H.C.Li,M.Belardi,D.Ren,S.Rodriguez,E.R.Bedja,D.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/21-Phosphatidylinositol 3-Kinase3',5'-Cyclic-GMP PhosphodiesteraseAnimalsAnimals,Newbornantagonists & inhibitorsBlood PressureCalcineurinCardiologyCardiomegalyConstrictionCyclic GMPCyclic GMP-Dependent Protein KinasesDNA-Binding Proteinsdrug effectsdrug therapyEnzyme ActivationenzymologyExtracellular Signal-Regulated MAP Kinasesgeneticsheartheart failureHemodynamic ProcesseshypertrophyMalemetabolismMiceMice,Inbred C57BLMice,TransgenicMyocardiumNFATC Transcription FactorsNuclear ProteinspathologypharmacologyPhosphodiesterase InhibitorsphysiologyPiperazinesPressureProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRatsRats,Sprague-Dawleyremodelingsildenafiltherapeutic useTranscription FactorsNot in File214222Nat.Med.112Nat.Med.1van de Schans2007686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyJournal686Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophyvan de Schans,V.van den Borne,S.W.Strzelecka,A.E.Janssen,B.J.van,der,VLangen,R.C.Wynshaw-Boris,A.Smits,J.F.Blankesteijn,W.M.2007/3Adaptor Proteins,Signal TransducinganalysisAnimalsAortic CoarctationAtrial Natriuretic Factorbeta CateninbiosynthesisCardiomegalycomplicationsConstrictionDisease Models,AnimaletiologyFemaleFrizzled ReceptorsGenesgeneticsGlycogen Synthase Kinase 3heartHypertensionhypertrophyMaleMiceMice,KnockoutNatriuretic PeptidespharmacologyPhosphoproteinsphysiologyphysiopathologyPressureProto-Oncogene Proteins c-aktResearchSignal TransductiontherapyultrasonographyWnt ProteinsNot in File473480Hypertension.493Hypertension.1Schroen2007690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophyJournal690Lysosomal integral membrane protein 2 is a novel component of the cardiac intercalated disc and vital for load-induced cardiac myocyte hypertrophySchroen,B.Leenders,J.J.van,Erk A.Bertrand,A.T.van,Loon M.van Leeuwen,R.E.Kubben,N.Duisters,R.F.Schellings,M.W.Janssen,B.J.Debets,J.J.Schwake,M.Hoydal,M.A.Heymans,S.Saftig,P.Pinto,Y.M.2007/5/21hypertrophyNot in Filei5J Cell Biol.1774J Cell Biol.1Sanada2007706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemJournal706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemSanada,S.Hakuno,D.Higgins,L.J.Schreiter,E.R.McKenzie,A.N.Lee,R.T.2007/6/1Angiotensin IIConstrictionfibroblastFibroblastsfibrosisheartheart failurehypertrophyMiceMyocardial InfarctionMyocardiumPhosphorylationPressureResearchsurvivalNot in File15381549J Clin.Invest.1176J Clin.Invest.1Chang2006355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisJournal355Activation of Rho-associated coiled-coil protein kinase 1 (ROCK-1) by caspase-3 cleavage plays an essential role in cardiac myocyte apoptosisChang,JiangXie,MinShah,Viraj R.Schneider,Michael D.Entman,Mark L.Wei,LeiSchwartz,Robert J.2006/9/26apoptosisheartheart failuremodelNot in File1449514500Proc.Natl.Acad.Sci.U.S.A.10339http://www.pnas.org/cgi/content/abstract/103/39/14495Proc.Natl.Acad.Sci.U.S.A.1Chen2006689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyJournal689The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophyChen,X.Shevtsov,S.P.Hsich,E.Cui,L.Haq,S.Aronovitz,M.Kerkela,R.Molkentin,J.D.Liao,R.Salomon,R.N.Patten,R.Force,T.2006/6Animalsbeta CateninCardiologyCardiomegalyCell CycleCell EnlargementCell ProliferationcytologydeficiencyetiologyGene DeletionGene Expressiongeneticsgrowth & developmentheartheart failurehypertrophyLymphoid Enhancer-Binding Factor 1metabolismMiceMice,Inbred C57BLMice,KnockoutMice,Mutant StrainsMice,TransgenicmodelMutationMyocytes,CardiacpathologyPhenotypeResearchSignal TransductionTCF Transcription FactorsTranscription FactorsNot in File44624473Mol.Cell Biol.2612Mol.Cell Biol.1Sun2007739Tumor Necrosis Factor-{alpha} Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload StateJournal739Tumor Necrosis Factor-{alpha} Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload StateSun,MeiChen,ManyinDawood,FayezZurawska,UrszulaLi,Jeff Y.Parker,ThomasKassiri,ZamanehKirshenbaum,Lorrie A.Arnold,MalcolmKhokha,RamaLiu,Peter P.2007/3/20apoptosisExtracellular Matrixfibrosisheart failureTAChypertrophyMiceVentricular RemodelingTNFNot in File13981407Circulation11511http://circ.ahajournals.org/cgi/content/abstract/115/11/1398Circulation1Asaumi2007740Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in MiceJournal740Protective Role of Endogenous Erythropoietin System in Nonhematopoietic Cells Against Pressure Overload-Induced Left Ventricular Dysfunction in MiceAsaumi,YasuhideKagaya,YutakaTakeda,MorihikoYamaguchi,NobuhiroTada,HirokoIto,KentaOhta,JunShiroto,TakashiShirato,KunioMinegishi,NaokoShimokawa,Hiroaki2007/4/17CapillarieserythropoetinMiceMyocardiumTACVEGFNot in File20222032Circulation11515http://circ.ahajournals.org/cgi/content/abstract/115/15/2022Circulation132-60Rodents and larger animalsfrequently combined with transgenic approaches and/or agonist infusion (ATII, Iso, PE, ET-1)
suppression of hypertrophy can be associated with enhanced systolic function ADDIN REFMGR.CITE Antos2002445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoJournal445Activated glycogen synthase-3 beta suppresses cardiac hypertrophy in vivoAntos,C.L.McKinsey,T.A.Frey,N.Kutschke,W.McAnally,J.Shelton,J.M.Richardson,J.A.Hill,J.A.Olson,E.N.2002/1/22AdultAnimalsCa(2+)-Calmodulin Dependent Protein KinaseCalcineurinCardiomegalyclinicalDNA-Binding ProteinsEnzyme ActivationetiologyGene ExpressiongeneticsGlycogen Synthase Kinase 3Glycogen Synthase Kinasesheartheart failurehypertrophyIsoproterenolmetabolismMiceMice,TransgenicModels,BiologicalMyocardiumMyosin Heavy ChainsNFATC Transcription FactorsNuclear Proteinspharmacologyprevention & controlSignal TransductionTranscription FactorsNot in File907912Proc.Natl.Acad.Sci.U.S.A.992Proc.Natl.Acad.Sci.U.S.A.1Hill2002596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionJournal596Targeted inhibition of calcineurin in pressure-overload cardiac hypertrophy. Preservation of systolic functionHill,J.A.Rothermel,B.Yoo,K.D.Cabuay,B.Demetroulis,E.Weiss,R.M.Kutschke,W.Bassel-Duby,R.Williams,R.S.2002/3/22Animalsantagonists & inhibitorsAortaBlood PressureBlotting,NorthernCalcineurinDNA,ComplementaryDose-Response Relationship,DrugechocardiographyElectroencephalographyheartHeart DiseasesHumanshypertrophyMalemetabolismMiceMice,TransgenicMyocardiumpathologyPressureProtein BindingProtein IsoformsRnaRNA,MessengerStressTime FactorsUp-RegulationNot in File1025110255J.Biol.Chem.27712Journal of Biological ChemistryJ.Biol.Chem.1Asakura2002667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyJournal667Cardiac hypertrophy is inhibited by antagonism of ADAM12 processing of HB-EGF: metalloproteinase inhibitors as a new therapyAsakura,M.Kitakaze,M.Takashima,S.Liao,Y.Ishikura,F.Yoshinaka,T.Ohmoto,H.Node,K.Yoshino,K.Ishiguro,H.Asanuma,H.Sanada,S.Matsumura,Y.Takeda,H.Beppu,S.Tada,M.Hori,M.Higashiyama,S.2002/1ADAM Proteinsanalogs & derivativesAngiotensin IIAnimalsantagonists & inhibitorsAorta,ThoracicCardiomegalyDisease Models,AnimalDisintegrinsdrug effectsdrug therapyEpidermal Growth FactorgeneticsGlycineGPCRGTP-Binding ProteinsheartHeart VentriclesHydroxamic AcidsHypertensionhypertrophyMaleMembrane ProteinsmetabolismMetalloendopeptidasesMicepharmacologyPhenylephrineProtease InhibitorsProtein Processing,Post-TranslationalRatsReceptor,Epidermal Growth FactorSignal TransductionsurgerySystoletherapeutic usetherapyTrans-Activation (Genetics)Not in File3540Nat.Med.81Nat.Med.1Takimoto2005677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyJournal677Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophyTakimoto,E.Champion,H.C.Li,M.Belardi,D.Ren,S.Rodriguez,E.R.Bedja,D.Gabrielson,K.L.Wang,Y.Kass,D.A.2005/21-Phosphatidylinositol 3-Kinase3',5'-Cyclic-GMP PhosphodiesteraseAnimalsAnimals,Newbornantagonists & inhibitorsBlood PressureCalcineurinCardiologyCardiomegalyConstrictionCyclic GMPCyclic GMP-Dependent Protein KinasesDNA-Binding Proteinsdrug effectsdrug therapyEnzyme ActivationenzymologyExtracellular Signal-Regulated MAP Kinasesgeneticsheartheart failureHemodynamic ProcesseshypertrophyMalemetabolismMiceMice,Inbred C57BLMice,TransgenicMyocardiumNFATC Transcription FactorsNuclear ProteinspathologypharmacologyPhosphodiesterase InhibitorsphysiologyPiperazinesPressureProtein-Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRatsRats,Sprague-Dawleyremodelingsildenafiltherapeutic useTranscription FactorsNot in File214222Nat.Med.112Nat.Med.1Sanada2007706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemJournal706IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling systemSanada,S.Hakuno,D.Higgins,L.J.Schreiter,E.R.McKenzie,A.N.Lee,R.T.2007/6/1Angiotensin IIConstrictionfibroblastFibroblastsfibrosisheartheart failurehypertrophyMiceMyocardial InfarctionMyocardiumPhosphorylationPressureResearchsurvivalNot in File15381549J Clin.Invest.1176J Clin.Invest.1Sun2007739Tumor Necrosis Factor-{alpha} Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload StateJournal739Tumor Necrosis Factor-{alpha} Mediates Cardiac Remodeling and Ventricular Dysfunction After Pressure Overload StateSun,MeiChen,ManyinDawood,FayezZurawska,UrszulaLi,Jeff Y.Parker,ThomasKassiri,ZamanehKirshenbaum,Lorrie A.Arnold,MalcolmKhokha,RamaLiu,Peter P.2007/3/20apoptosisExtracellular Matrixfibrosisheart failureTAChypertrophyMiceVentricular RemodelingTNFNot in File13981407Circulation11511http://circ.ahajournals.org/cgi/content/abstract/115/11/1398Circulation136-38;42;58;59
neurohormonal activation due to decreased renal perfusion) is superimposed on increased afterloadIschemia
Reperfusion ADDIN REFMGR.CITE Orlic2001593Bone marrow cells regenerate infarcted myocardiumJournal593Bone marrow cells regenerate infarcted myocardiumOrlic,D.Kajstura,J.Chimenti,S.Jakoniuk,I.Anderson,S.M.Li,B.Pickel,J.McKay,R.Nadal-Ginard,B.Bodine,D.M.Leri,A.Anversa,P.2001/4/5AnimalsBone Marrow CellsBone Marrow TransplantationCell DifferentiationConnexin 43cytologyDNA-Binding ProteinsFemalegeneticsGreen Fluorescent ProteinsheartKi-67 AntigenLigationLuminescent ProteinsMalemetabolismMiceMice,Inbred C57BLMice,TransgenicMyocardial InfarctionMyocardiumMyogenic Regulatory FactorspathologyProto-Oncogene Proteins c-kitStem CellstherapyTranscription FactorsNot in File701705Nature.4106829Nature.1Edelberg2002587Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heartJournal587Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heartEdelberg,J.M.LEE,S.H.Kaur,M.Tang,L.Feirt,N.M.McCabe,S.Bramwell,O.Wong,S.C.Hong,M.K.2002/2/5Age FactorsAgingAnimalsAnimals,NewbornbiosynthesisCells,CulturedclinicalCoculture TechniquesCoronary VesselscytologyDisease Models,Animaldrug effectsEndothelial CellsEndothelium,VasculargeneticsGraft SurvivalheartHeart TransplantationLigationmetabolismmethodsMiceMice,Inbred C57BLmodelMyocardial InfarctionMyocardiumNeovascularization,PhysiologicpathologyPDGFpharmacologyPhenotypephysiologyPlatelet-Derived Growth Factorprevention & controlProto-Oncogene Proteins c-sisRatsReverse Transcriptase Polymerase Chain ReactiontherapyNot in File608613Circulation.1055Circulation.1Hsieh2006588Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicityJournal588Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicityHsieh,P.C.MacGillivray,C.Gannon,J.Cruz,F.U.Lee,R.T.2006/8/15administration & dosageadverse effectsAnimalschemically inducedDrug Delivery Systemsdrug effectsdrug therapyechocardiographyheartheart failureHemodynamic ProcessesHypertensionHypertension,PulmonaryInjectionsLungMalemethodsMyocardial InfarctionMyocardiumNanotechnologyNOPDGFpharmacologyphysiologyphysiopathologyPlatelet-Derived Growth Factorprevention & controlPulmonary Arterypulmonary hypertensionRandom AllocationRatsRats,Sprague-DawleyRegional Blood FlowsurgerytherapytoxicityVentricular FunctionNot in File637644Circulation.1147Circulation.1Black1998535Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the ratJournal535Co-localization of the cysteine protease caspase-3 with apoptotic myocytes after in vivo myocardial ischemia and reperfusion in the ratBlack,S.C.Huang,J.Q.Rezaiefar,P.Radinovic,S.Eberhart,A.Nicholson,D.W.Rodger,I.W.1998/4analysisAnimalsapoptosisCaspase 3CaspasesCell DeathCysteineCysteine EndopeptidasescytologyDnaDNA FragmentationenzymologyheartHeart VentriclesischemiaMalemodelMyocardial IschemiaMyocardial ReperfusionMyocardiumpharmacologyphysiopathologyRatsRats,Sprague-DawleyResearchSodiumNot in File733742J.Mol.Cell Cardiol.304J.Mol.Cell Cardiol.1Yaoita1998462Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitorJournal462Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitorYaoita,H.Ogawa,K.Maehara,K.Maruyama,Y.1998/1/27administration & dosageAmino Acid Chloromethyl KetonesAnimalsapoptosiscomplicationsCysteineCysteine EndopeptidasesCysteine Proteinase InhibitorscytologyDisease Models,AnimalDnadrug effectsdrug therapyElectrophoresisElectrophoresis,Agar GeletiologyGenetic TechniquesheartHemodynamic ProcessesLeukocyte CountMalemetabolismmethodsMyocardial InfarctionMyocardial IschemiaMyocardial Reperfusion InjuryMyocardiumpathologypharmacologyphysiopathologyRatsRats,Sprague-DawleyReperfusion InjuryRiskNot in File276281Circulation.973Circulation.1Holly1999463Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivoJournal463Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion in vivoHolly,T.A.Drincic,A.Byun,Y.Nakamura,S.Harris,K.Klocke,F.J.Cryns,V.L.1999/9Amino Acid Chloromethyl KetonesAnimalsapoptosisCaspase 1Caspase 2Caspase 7CaspasesCell DeathCysteine Proteinase InhibitorscytologyEnzyme ActivationenzymologyIn Situ Nick-End LabelingischemiametabolismMyocardial InfarctionMyocardial IschemiaMyocardial ReperfusionMyocardial Reperfusion InjuryMyocardiumpathologypharmacologyPoly(ADP-ribose) PolymerasesRabbitsNot in File17091715J.Mol.Cell Cardiol.319J.Mol.Cell Cardiol.163-68Rodents and larger animalsmay enhance understanding of pathobiology of PAH associated right heart failureTAC = transverse aortic constriction; ATII = angiotensin II; Iso = isoproterenol; PE = phenylepinephrine; ET-1 = endothelin-1; PAH = pulmonary arterial hypertension.
Legends to the figures
Figure e1. Excitation-contraction coupling. Cytosolic Ca2+ enters the sarcoplasimic reticulum (SR) through L-type Ca2+ channels (LTCCs). The resultant increase in intracellular Ca2+ triggers further Ca2+ release from the SR through the ryanodine receptor (RyR). Intracellular Ca2+ binds to troponin C within the myofilaments, which initiates contraction (not shown). Subsequent relaxation depends on dissociation of Ca2+ from troponin C and Ca2+ reuptake by the SR through a Ca2+-ATPase (SERCA), interacting with phospholamban. Ca2+ is removed trans-sarcolemmally through the Na/Ca2+ exchanger (not shown). Unphosphorylated phospholamban inhibits SERCA, and by phosphorylating phospholamban, protein kinase A (PKA) enhances SERCA-mediated Ca2+ re-entry into the SR during diastole.
Figure e2. G prot e i n c o u p l e d r e c e p t o r s ( G P C R s ) i n v o l v e d i n t h e m y o c a r d i a l h y p e r t r o p h i c r e s p o n s e . D i f f e r e n t r e c e p t o r t y p e s u s e d i f f e r e n t s e c o n d a r y m e s s e n g e r s . O n e o f t h e c o n s e q u e n c e s o f a n g i o t e n s i n I I ( A T I I ) b i n d i n g t o t h e a n g i o t e n s i n t y p e 1 r e c e p t o r ( A T 1 R ) i s a c t i v a t i o n o f p h o s p h o l i p a s e C ( P L C ) , w h i c h i s f o l l o w e d b y a n i n c r e a s e i n i n t r a c e l l u l a r C a 2 + a n d p r o t e i n k i n a s e C ( P K C ) a c t i v a t i o n . A f t e r b i n d i n g o f c a t e c h o l a m i n e s t o t h e - a d r e n e r g i c r e c e p t o r ( - A R ) , a d e n y l a t e c y c l a s e i s a c t i v a t e d , c A M P i s p r o d u c e d a n d p r o t e i n k i n a se A is activated. Other consequences of GPCR activation are activation of small GTP binding proteins (GTPases) and MAPK cascades. See text for more details.
Figure e3. The central role of cGMP/PKG signaling in the attenuation of myocardial hypertrophy. Activation of particulate gyanylate cyclase (pGC) by natriuretic peptides and soluble gyanylate cyclase (sGC) by nitric oxide is followed by production of cGMP and activation of protein kinase G (PKG). PKG affects myocardial contractility by reducing cAMP c o n c e n t r a t i o n s t h r o u g h i n h i b i t i o n o f a d e n y l a t e c y c l a s e a n d t h e i n d u c t i o n o f p h o s p h o d i e s t e r a s e P D E 2 . T h e p r o d u c t i o n o f p r o - h y p e r t r o p h i c t r a n s c r i p t i o n f a c t o r s t h a t u l t i m a t e l y f o l l o w s A T 1 R a n d - A R a c t i v a t i o n i s c o u n t e r b a l a n c e d b y c G M P / P K G s i g n a l i n g . c G M P / P K G signaling blunts the hypertrophic response through inhibition of the calcineurin/NFAT pathway, PI3K/Akt1 signaling (not shown), MAPK cascades and Rho signaling.
Figure e4. Wnt signaling and the balance between growth and angiogenesis. After Wnt ligands bind to a membrane-bound complex consisting of a member of the Fz receptor family and a LDL receptorrelated protein (LRP), a member of the disheveled (Dvl) protein family is activated. This prevents inhibition of pro-hypertrophic transcription factors and d e c r e a s e s p h o s p h o r y l a t i o n o f - c a t e n i n b y G S K - 3 . - c a t e n i n a c c u m u l a t e s i n t h e c y t o p l a s m a n d i s t r a n s f e r r e d t o t h e n u c l e u s , w h e r e i t c o m b i n e s w i t h T c f / L e f t o i n d u c e g r o w t h ( p r o l i f e r a t i o n o r h y p e r t r o p h y ) . H o w e v e r , i n h y p o x i c c o n d i t i o n s - c a t e n i n c o m b i n e s w i t h h y p o x i a i n d u c i b l e f a c t o r ( H I F ) - 1 t o i n d u c e c e l l c y c l e a r r e s t a n d a n g i o g e n e s i s . H y p o x i a p r e v e n t s u b i q u i t i n a t i o n o f H I F - 1 a n d o c c u r s w h e n a n g i o g e n e s i s i s i n s u f f i c i e n t i n c o m p a r i s o n t o t h e d e g r e e o f g r o w t h . I n n o r m o x i c c o n d i t i o n s , H I F - 1 i s h y d r o x y l a t e d b y p r o l y l h y d r o x y l a s e s w h i c h a l l o w s b i n d i n g o f v o n H i p p e l - L i n d a u p r o t e i n ( V H L ) . H I F - 1 i s s u b s e q u e n t l y u b i q u i t i n a t e d i n t h e p r o t e o s o m e .
F i g u r e e 5 . T h e p o s s i b l e r o l e o f A k t 1 s i g n a l i n g i n t h e t r a n s i t i o n f r o m c o m p e n s a t e d h y p e r t r o p h y t o d i l a t a t i o n a n d f a i l u r e of the pressure overloaded right ventricle. An increased right ventricular afterload is associated with Akt1 signaling (e.g. induced by G protein coupled receptors or receptor tyrosine kinases) and subsequent activation of hypertrophic transcription factors. Hypertrophy must be met with angiogenesis to prevent ischemia, and this is realized by hypoxic prevention of hypoxia inducible factor (HIF)- 1 u b i q u i t i n a t i o n a n d s u b s e q u e n t v a s c u l a r e n d o t h e l i a l g r o w t h f a c t o r ( V E G F ) t r a n s c r i p t i o n . H o w e v e r , p r o l o n g e d A k t 1 s i g n a l i n g l e a d s t o u p r e g u l a t i o n o f t h e t u m o r s u p p r e s s o r g e n e p 5 3 , w h i c h i n h i b i t s H I F - 1 i n d e p e n d e n t l y f r o m o x y g e n c o n c e n t r a t i o n s . C o p p e r i s a n o t h e r o x y g e n i n d e p e n d e n t r e g u l a t o r o f H I F - 1 a n d t h e c o p p e r d e f i c i e n c y t h a t m a y o c c u r i n h e a r t f a i l u r e c o n t r i b u t e s t o i n s u f f i c i e n t a n g i o g e n e s i s .
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