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Jos J. Fuster a, Javier Dez b and Vicente Andrs a
a Laboratory of Vascular Biology, Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia, Consejo Superior de Investigaciones Cientficas, 46010 Valencia, Spain
b Division of Cardiovascular Sciences, Centre for Applied Medical Research; Department of Cardiology and Cardiovascular Surgery, University Clinic, School of Medicine, University of Navarra, Pamplona, Spain.
SHORT TITLE: Telomeres and Hypertension
WORD COUNT: 5,908 (excluding figure legends)
SOURCES OF FUNDING: Work in the author's laboratories is supported in part by grants from Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III (Red Temtica de Investigacin Cooperativa Cardiovascular RECAVA), and from the Ministerio de Educacin y Ciencia and the European Regional Development Fund (SAF2004-03057). J.J.F. is supported by a CSIC-I3P predoctoral fellowship cosponsored by the European Social Fund.
CONFLICT(S) OF INTEREST: None
SEND CORRESPONDENCE TO:
Vicente Andrs, PhD
Laboratory of Vascular Biology
Instituto de Biomedicina de Valencia (IBV-CSIC)
C/Jaime Roig 11, 46010 Valencia (Spain)
Tel: +34-96-3391752 FAX: +34-96-3391751 E-mail: vandres@ibv.csic.es
Abstract
Aging is a major risk factor for hypertension and associated cardiovascular disease. In most proliferative tissues, aging is characterized by shortening of the DNA component of telomeres, the specialized genetic segments that cap the end of eukaryotic chromosomes and protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, telomere shortening is thought to contribute to organismal aging and to the development of age-related diseases. Here, we review animal and human studies that have investigated possible links between telomere ablation and the pathogenesis of hypertension and related target organ damage. Whilst evidence is mounting that alterations in telomerase activity and telomere shortening may play a role in the pathogenesis of hypertension, additional studies are required to understand the molecular mechanisms by which telomere dysfunction and hypertension are functionally connected. As our knowledge on this emerging field grows, the challenge will be to ascertain whether all this information might translate into clinical applications.
KEY WORDS: Telomeres, telomerase, hypertension, hypertensive heart disease, nephroangiosclerosis, atherosclerosis, oxidative stress.
Introduction
Parallel structural and functional changes in the large arteries (stiffness), cardiac mass (hypertrophy), and myocardial relaxation and filling (diastolic dysfunction) occur in normotensive aging and hypertension at any age. This continuum of age-related change is simply accelerated in individuals with chronic hypertension, so that the same changes occur at an earlier age or to an exaggerated degree. In this regard, the traditional clinical distinction between normotension and hypertension is quite arbitrary, although it may be useful with regard to cardiovascular risk stratification. In fact, the similarities between aging and hypertension are so striking that aging can be considered to be muted hypertension, while hypertension can be likened to accelerated aging. It is imperative, therefore, to introduce biological indicators of aging into models developed to provide a better understanding of the pathophysiology of essential hypertension. One of these indicators may well be the age-dependent telomere length in somatic cells.
Telomeres are specialized chromatin structures that cap the ends of eukaryotic chromosomes and prevent the recognition of chromosomal ends as double stranded DNA breaks. Thus, functional telomeres are essential to avoid a DNA damage cellular response resulting from chromosome recombination and degradation. Telomeres contain a large number of non-coding double-stranded repeats of G-rich tandem DNA sequences (TTAGGG in vertebrates) spanning 10-15 kb in humans and 25-40 kb in mice, which end in a 150-200 nucleotide 3' single-stranded overhang (G-strand overhang) ADDIN EN.CITE Blackburn200110210217Blackburn, E. H.Department of Biochemistry and Biophysics, University of California, San Francisco, 94143, USA. telomer@itsa.ucsf.eduSwitching and signaling at the telomereCell661-6731066AnimalDNA ReplicationDNA-Binding Proteins/chemistry/metabolismHumanModels, GeneticSaccharomyces cerevisiae/geneticsSignal TransductionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomerase/*metabolismTelomere/*physiology/*ultrastructure2001Sep 2111572773http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11572773Blasco200525425417Blasco, M. A.Telomeres and human disease: ageing, cancer and beyondNat Rev Genet611-22682005[1, 2]. Telomere-associated proteins include the telomerase components TERC (telomerase RNA component, which serves as a template for the synthesis of new telomeric repeats) and TERT (telomerase reverse transcriptase component, which catalyzes the synthesis of new telomeric repeats). 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Due to the so-called end replication problem, cells with scarce or absent telomerase activity display progressive telomere attrition with each mitotic cycle, hence telomere length in somatic cells reflects their replicative history and can predict their remaining proliferative potential. Cells with critically short telomeres undergo chromosomal end-to-end fusions, replicative senescence, and apoptosis ADDIN EN.CITE Harrington200231331317Harrington, L.Robinson, M. 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D.Department of Medicine, Division of Hematology and Cancer Biology Program, Stanford University School of Medicine, Stanford, CA 94305, USA. sartandi@stanford.eduPathways connecting telomeres and p53 in senescence, apoptosis, and cancerBiochem Biophys Res CommunBiochem Biophys Res Commun881-890331Aging/*physiologyAnimalsApoptosis/*physiologyChromosomal Instability/physiologyDNA Damage/physiologyG1 PhaseGenes, p53HumansMiceNeoplasms/*physiopathologySignal TransductionTelomerase/physiologyTelomere/*physiologyTumor Suppressor Protein p53/*physiology200515865944http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15865944 [6, 7].
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W.Cold Spring Harbor Laboratory, NY 11724, USA.Developmental and tissue-specific regulation of mouse telomerase and telomere lengthProc Natl Acad Sci U S A4818-48229211AnimalAnimals, NewbornBrain/enzymologyCell AgingCell DivisionCells, CulturedComparative StudyDNA Nucleotidylexotransferase/*metabolismFibroblasts/cytology/enzymologyHumanKineticsLiver/enzymologyMaleMiceMice, Inbred BALB CMice, Inbred StrainsMuridaeOrgan SpecificitySkin/*cytology/*enzymologySpecies SpecificitySpleen/enzymologySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.*TelomereTestis/enzymology1995May 237761406http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7761406[8, 9] and humans ADDIN EN.CITE Okuda200211321317Okuda, KojiBardeguez, ArleneGardner, Jeffrey P.Rodriguez, PauletteGanesh, VijayaKimura, MasayukiSkurnick, JoanAwad, GirgisAviv, AbrahamTelomere Length in the NewbornPediatr Res377-3815232002August 21, 2002http://www.pedresearch.org/cgi/content/abstract/52/3/377 10.1203/01.pdr.0000022341.72856.72Slagboom199411011017Slagboom, P. 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H.Aviv, A.Hypertension Research Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103-2714, USA.Telomere length inversely correlates with pulse pressure and is highly familialHypertension195-200362AdolescentAdultBlood Pressure/genetics/*physiologyDNA/geneticsDiastoleFamily HealthFemaleHumanMaleMultivariate AnalysisPolymorphism, Restriction Fragment Length*PulseRegression AnalysisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.SystoleTelomere/*genetics2000Aug10948077http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10948077Takubo2002868617Takubo, K.Izumiyama-Shimomura, N.Honma, N.Sawabe, M.Arai, T.Kato, M.Oshimura, M.Nakamura, K.Department of Clinical Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, 173 0015, Japan. takubo@tmig.or.jpTelomere lengths are characteristic in each human individualExp Gerontol523-531374AdolescentAdultAgedAged, 80 and overBlotting, SouthernBrain/ultrastructureChildChild, PreschoolDNA/analysisElectrophoresis, Gel, Pulsed-FieldFemaleHumanInfantKidney/ultrastructureLiver/ultrastructureMaleMiddle AgeMyocardium/ultrastructureRegression AnalysisSupport, Non-U.S. Gov't*Telomere2002Apr11830355http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11830355[10-14]. Although evidence exists suggesting that individual telomere length is influenced by genetic factors ADDIN EN.CITE Slagboom199411011017Slagboom, P. E.Droog, S.Boomsma, D. I.TNO-PG Department of Vascular and Connective Tissue Research, Leiden, Netherlands.Genetic determination of telomere size in humans: a twin study of three age groupsAm J Hum Genet876-882555AdolescentAdultAgedAged, 80 and overAging/*geneticsBlotting, SouthernChildChild, PreschoolHumanMiddle AgeRepetitive Sequences, Nucleic AcidTelomere/*genetics1994Nov7977349http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7977349Jeanclos2000979717Jeanclos, E.Schork, N. J.Kyvik, K. O.Kimura, M.Skurnick, J. H.Aviv, A.Hypertension Research Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103-2714, USA.Telomere length inversely correlates with pulse pressure and is highly familialHypertension195-200362AdolescentAdultBlood Pressure/genetics/*physiologyDNA/geneticsDiastoleFamily HealthFemaleHumanMaleMultivariate AnalysisPolymorphism, Restriction Fragment Length*PulseRegression AnalysisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.SystoleTelomere/*genetics2000Aug10948077http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10948077Nawrot200414114117Nawrot, T. S.Staessen, J. A.Gardner, J. P.Aviv, A.Study Coordinating Centre, Laboratory of Hypertension, Department of Molecular and Cardiovascular Research, University of Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.Telomere length and possible link to X chromosomeLancetLancet507-510363AdultAging/*genetics/physiologyBase CompositionBelgiumChromosomes, Human, X/*genetics/ultrastructureCohort StudiesComparative StudyFamilyFemaleHumanLeukocytes/physiology/ultrastructureMaleMarriageMiddle AgedPedigreeRestriction Mapping/methodsSampling StudiesSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Tandem Repeat Sequences/genetics/physiologyTelomere/*genetics/ultrastructure200414975611http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14975611[11, 13, 15], evidence is mounting that the effects of environmental factors on the rate of telomere exhaustion may also be of great importance in determining telomere length in adulthood ADDIN EN.CITE Fuster200628928917Fuster, Jose J.Andres, VicenteTelomere Biology and Cardiovascular DiseaseCirc Res1167-118099112006November 24, 2006http://circres.ahajournals.org/cgi/content/abstract/99/11/1167 10.1161/01.res.0000251281.00845.18[16]. It has also been shown that females display higher telomerase activity ADDIN EN.CITE Leri2000757517Leri, A.Malhotra, A.Liew, C. C.Kajstura, J.Anversa, P.Department of Medicine, New York Medical College, Valhalla, NY 10595, USA. annarisa_leri@nymc.eduTelomerase activity in rat cardiac myocytes is age and gender dependentJ Mol Cell Cardiol385-39032Aging/*metabolismAnimalCell SeparationFemaleMaleMyocardium/cytology/*enzymologyRatsRats, Inbred F344Sex FactorsSupport, U.S. Gov't, P.H.S.Telomerase/*metabolism200010731438http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10731438[17] and longer telomeres ADDIN EN.CITE Coviello-McLaughlin199710810817Coviello-McLaughlin, G. M.Prowse, K. R.Geron Corporation, 200 Constitution Drive, Menlo Park, CA 94025, USA.Telomere length regulation during postnatal development and ageing in Mus spretusNucleic Acids Res3051-30582515Aging/*geneticsAnimalFemaleMaleMiceMice, Inbred C57BLMuridaeSex CharacteristicsTelomerase/metabolism*Telomere1997Aug 19224604http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9224604Benetos2001969617Benetos, A.Okuda, K.Lajemi, M.Kimura, M.Thomas, F.Skurnick, J.Labat, C.Bean, K.Aviv, A.Center "Investigations Preventives et Cliniques" (IPC), INSERM U337, Paris, France. benetos@ipc.asso.frTelomere length as an indicator of biological aging: The gender effect and relation with pulse pressure and pulse wave velocityHypertension381-5372*Aging/genetics/physiologyBlood Flow VelocityBlood PressureBody Mass IndexCohort StudiesFemaleHumanMaleMiddle AgeMultivariate AnalysisPulsatile FlowSex FactorsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomere/*geneticsTengoHipertension2001Feb11230193http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11230193Cherif200310910917Cherif, H.Tarry, J. 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H.Aviv, A.Hypertension Research Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103-2714, USA.Telomere length inversely correlates with pulse pressure and is highly familialHypertension195-200362AdolescentAdultBlood Pressure/genetics/*physiologyDNA/geneticsDiastoleFamily HealthFemaleHumanMaleMultivariate AnalysisPolymorphism, Restriction Fragment Length*PulseRegression AnalysisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.SystoleTelomere/*genetics2000Aug10948077http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10948077[8, 13, 18, 19] in various adult tissues compared with age-matched males possibly due, at least in part, to estrogen-dependent activation of telomerase ADDIN EN.CITE Kyo199911411417Kyo, S.Takakura, M.Kanaya, T.Zhuo, W.Fujimoto, K.Nishio, Y.Orimo, A.Inoue, M.Department of Obstetrics and Gynecology, School of Medicine, Kanazawa University, Ishikawa, Japan. satoruky@med.kanazawa-u.ac.jpEstrogen activates telomeraseCancer Res5917-59215923Base SequenceBinding SitesBreast NeoplasmsEnzyme ActivationEstradiol/*pharmacologyFemaleGene Expression Regulation, Enzymologic/drug effectsGene Expression Regulation, Neoplastic/drug effectsGenes, ReporterHumanLuciferase/geneticsPolymerase Chain Reaction*Promoter Regions (Genetics)Receptors, Estrogen/metabolismTelomerase/*genetics/*metabolismTransfectionTumor Cells, Cultured1999Dec 110606235http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10606235Imanishi200525525517Imanishi, T.Hano, T.Nishio, I.Department of Cardiovascular Medicine, Wakayama Medical University, 811-1 Kimidera, Wakayama City, Wakayama 641-8510, Japan. t-imani@wakayama-med.ac.jpEstrogen reduces endothelial progenitor cell senescence through augmentation of telomerase activityJ HypertensJ Hypertens1699-706239Androstadienes/pharmacologyBlotting, WesternCell Aging/*drug effectsCell Division/drug effectsCells, CulturedChromones/pharmacologyCollagen/metabolismComparative StudyDNA-Binding Proteins/metabolismDose-Response Relationship, DrugDrug CombinationsEndothelium, Vascular/cytologyEnzyme Inhibitors/pharmacologyEnzyme-Linked Immunosorbent AssayEstrogens/*pharmacologyHumansLaminin/metabolismMorpholines/pharmacologyPhosphorylation/drug effectsProtein-Serine-Threonine Kinases/metabolismProteoglycans/metabolismProto-Oncogene Proteins/metabolismProto-Oncogene Proteins c-aktResearch Support, Non-U.S. Gov'tReverse Transcriptase Polymerase Chain ReactionStem Cells/*cytology/*drug effects/metabolismTelomerase/*metabolismVascular Endothelial Growth Factor A/pharmacology/secretionbeta-Galactosidase/metabolism2005Sep16093915http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16093915 [20, 21].
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A.Department of Immunology and Oncology, National Centre of Biotechnology, Madrid 28049, Spain.Decreased B16F10 melanoma growth and impaired vascularization in telomerase-deficient mice with critically short telomeresCancer Res552-55962AnimalApoptosis/physiologyCell Division/physiologyCollagenDrug CombinationsFemaleLamininMaleMelanoma, Experimental/*blood supply/enzymology/pathologyMiceMice, Inbred C57BLNeovascularization, Pathologic/*enzymology/pathologyProteoglycansSupport, Non-U.S. Gov'tTelomerase/*deficiency/geneticsTelomere/*physiology200211809709http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11809709Leri2003131317Leri, A.Franco, S.Zacheo, A.Barlucchi, L.Chimenti, S.Limana, F.Nadal-Ginard, B.Kajstura, J.Anversa, P.Blasco, M. A.Department of Medicine, Cardiovascular Research Institute, New York Medical College, Valhalla, NY 10595, USA.Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulationEmbo J131-13922AnimalCells, CulturedDisease Models, AnimalGene Expression Regulation*Genes, p53Heart/*physiology/physiopathologyHeart Failure, Congestive/*geneticsHumanMiceMice, KnockoutMuscle Cells/cytology/physiologyProtein p53/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomerase/*deficiency/*genetics/metabolismTelomere/*genetics/ultrastructureVasodilation/*genetics200312505991http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12505991Wong2003414117Wong, K. K.Maser, R. S.Bachoo, R. M.Menon, J.Carrasco, D. R.Gu, Y.Alt, F. W.DePinho, R. A.Department of Adult Oncology, Dana Farber Cancer Institute Boston, Massachusetts 02115, USA.Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageingNature643-648421Aging/*geneticsAlopecia/geneticsAnaphaseAnimalApoptosisCell DivisionCells, CulturedFibroblastsHair Color/geneticsHomeostasis/*geneticsLymphoma, T-Cell/geneticsMiceMice, KnockoutProtein p53/metabolismProtein-Serine-Threonine Kinases/deficiency/*geneticsRNA/*geneticsStem Cells/cytology/metabolismSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Survival RateTelomerase/*geneticsTelomere/enzymology/genetics/*metabolismWound Healing/genetics200312540856http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12540856Perez-Rivero200625725717Perez-Rivero, G.Ruiz-Torres, M. P.Rivas-Elena, J. V.Jerkic, M.Diez-Marques, M. L.Lopez-Novoa, J. M.Blasco, M. A.Rodriguez-Puyol, D.Research Unit, Principe de Asturias Hospital, Alcala de Henares, Madrid, Spain.Mice deficient in telomerase activity develop hypertension because of an excess of endothelin productionCirculationCirculation309-1711442006Jul 2516831983http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16831983 [22-29], thus supporting the concept that progressive telomere shortening might be involved in the pathogenesis of age-related human disorders. Of note in this regard, telomerase activity is impaired, or telomere attrition is accelerated, in various human premature aging syndromes, such as dyskeratosis congenita ADDIN EN.CITE Vulliamy200127127117Vulliamy, T.Marrone, A.Goldman, F.Dearlove, A.Bessler, M.Mason, P. J.Dokal, I.Department of Haematology, Division of Investigative Science, Faculty of Medicine, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, Ducane Road, London W12 ONN, UK.The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenitaNature432-54136854Cell LineChromosome Mapping*Chromosomes, Human, Pair 3DNA Mutational AnalysisDyskeratosis Congenita/*geneticsFemaleGenes, DominantHumansLinkage (Genetics)Male*MutationPedigreePoint MutationRNA/*geneticsResearch Support, Non-U.S. Gov'tTelomerase/*geneticsTelomere2001Sep 2711574891http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11574891 [30]. Werner syndrome ADDIN EN.CITE Chang200427227217Chang, SandyMultani, Asha S.Cabrera, Noelia G.Naylor, Maria L.Laud, PurnimaLombard, DavidPathak, SenGuarente, LeonardDePinho, Ronald A.Essential role of limiting telomeres in the pathogenesis of Werner syndromeNat Genet877-8823682004http://dx.doi.org/10.1038/ng1389http://www.nature.com/ng/journal/v36/n8/suppinfo/ng1389_S1.html [31] or ataxia telangectasia ADDIN EN.CITE Metcalfe199627327317Metcalfe, Judith A.Parkhill, JulianCampbell, LouiseStacey, MichaelBiggs, PaulByrd, Philip J.Taylor, A. Malcolm R.Accelerated telomere shortening in ataxia telangiectasiaNat Genet350-3531331996http://dx.doi.org/10.1038/ng0796-350 [32]. The importance of telomerase deficit on the pathogenesis of these disorders is emphasized by the observation that ectopic expression of telomerase in cultured cells obtained from dyskeratosis congenita patients rescues telomere defects ADDIN EN.CITE Wong200629129117Wong, J. M.Collins, K.Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA.Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenitaGenes Dev2848-582020AnimalsCell Cycle Proteins/metabolismCell ProliferationChromosomes, Human, X/*ultrastructureDyskeratosis Congenita/*genetics/*pathologyFibroblasts/metabolismHumansKineticsMiceNuclear Proteins/metabolism*RnaRNA, Ribosomal/chemistry/metabolismRibosomes/metabolismTelomerase/*chemistry/metabolismTelomere/*ultrastructure2006Oct 1517015423http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17015423 [33].
Relationships between human telomere length and blood pressure parameters
Several population-based studies have assessed the relations of blood pressure parameters with telomere length in white blood cells (WBCs). In a study that included 49 normotensive twin pairs (38 men and 60 women, 18 to 44 years of age), Jeanclos et al ADDIN EN.CITE Jeanclos2000979717Jeanclos, E.Schork, N. J.Kyvik, K. O.Kimura, M.Skurnick, J. H.Aviv, A.Hypertension Research Center, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark 07103-2714, USA.Telomere length inversely correlates with pulse pressure and is highly familialHypertension195-200362AdolescentAdultBlood Pressure/genetics/*physiologyDNA/geneticsDiastoleFamily HealthFemaleHumanMaleMultivariate AnalysisPolymorphism, Restriction Fragment Length*PulseRegression AnalysisSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.SystoleTelomere/*genetics2000Aug10948077http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10948077[13] found that telomere restriction fragment length in WBCs correlated positively with diastolic blood pressure (DBP) but negatively with both systolic blood pressure (SBP) and pulse pressure (PP=SBPDBP). Telomere length and PP were highly familial and the correlation observed between these parameters was gender-independent. By analyzing 120 men (SBP=134.8(1.5 mm Hg; DBP=85.2(0.9; mean age=551 years) and 73 women (SBP=131.2(1.9 mm Hg; DBP=81.3(1.2; mean age=561 years) who were not on any hypertensive medication, Benetos et al ADDIN EN.CITE Benetos2001969617Benetos, A.Okuda, K.Lajemi, M.Kimura, M.Thomas, F.Skurnick, J.Labat, C.Bean, K.Aviv, A.Center "Investigations Preventives et Cliniques" (IPC), INSERM U337, Paris, France. benetos@ipc.asso.frTelomere length as an indicator of biological aging: The gender effect and relation with pulse pressure and pulse wave velocityHypertension381-5372*Aging/genetics/physiologyBlood Flow VelocityBlood PressureBody Mass IndexCohort StudiesFemaleHumanMaleMiddle AgeMultivariate AnalysisPulsatile FlowSex FactorsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomere/*geneticsTengoHipertension2001Feb11230193http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11230193[18] found a negative correlation between age and telomere length in both sexes. However, shorter telomeres appeared to contribute to increased PP and arterial stiffness only in men ADDIN EN.CITE Benetos2001969617Benetos, A.Okuda, K.Lajemi, M.Kimura, M.Thomas, F.Skurnick, J.Labat, C.Bean, K.Aviv, A.Center "Investigations Preventives et Cliniques" (IPC), INSERM U337, Paris, France. benetos@ipc.asso.frTelomere length as an indicator of biological aging: The gender effect and relation with pulse pressure and pulse wave velocityHypertension381-5372*Aging/genetics/physiologyBlood Flow VelocityBlood PressureBody Mass IndexCohort StudiesFemaleHumanMaleMiddle AgeMultivariate AnalysisPulsatile FlowSex FactorsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomere/*geneticsTengoHipertension2001Feb11230193http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11230193[18]. More recently, Demissie et al ADDIN EN.CITE Demissie200625325317Demissie, S.Levy, D.Benjamin, E. J.Cupples, L. A.Gardner, J. P.Herbert, A.Kimura, M.Larson, M. G.Meigs, J. B.Keaney, J. F.Aviv, A.Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart StudyAging Cell325-330542006http://www.blackwell-synergy.com/doi/abs/10.1111/j.1474-9726.2006.00224.x doi:10.1111/j.1474-9726.2006.00224.x[34] corroborated the association between hypertension and shorter leukocyte telomere length in 327 men from the Framingham Heart study, and suggested that this relationship is largely due to insulin resistance, a disorder frequently associated with hypertension ADDIN EN.CITE Sowers200428828817Sowers, J. R.Frohlich, E. D.Insulin and insulin resistance: impact on blood pressure and cardiovascular diseaseMed Clin North Am63-828812004Saad200428728717Saad, Mohammed F.Rewers, MarianSelby, JosephHoward, GeorgeJinagouda, SujataFahmi, SalwaZaccaro, DanBergman, Richard N.Savage, Peter J.Haffner, Steven M.Insulin Resistance and Hypertension: The Insulin Resistance Atherosclerosis StudyHypertension1324-13314362004June 1, 2004http://hyper.ahajournals.org/cgi/content/abstract/43/6/1324 10.1161/01.HYP.0000128019.19363.f9[35, 36].
Recent studies in 419 older adults (mean age=74.25.2 years) from the Cardiovascular Health Study cohort followed during 10 years showed a borderline inverse association (p value of 0.06) between WBC telomere length and DBP ADDIN EN.CITE Fitzpatrick200729629617Fitzpatrick, A. L.Kronmal, R. A.Gardner, J. P.Psaty, B. M.Jenny, N. S.Tracy, R. P.Walston, J.Kimura, M.Aviv, A.Department of Epidemiology, School of Public Health and Community Medicine, Collaborative Health Studies Coordinating Center, University of Washington, Seattle, WA 98115, USA. fitzpal@u.washington.eduLeukocyte telomere length and cardiovascular disease in the cardiovascular health studyAm J Epidemiol14-2116512007Jan 117043079http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17043079 [37]. Although the association pointed in the direction one would expect if longer telomeres corresponded with a better blood pressure status, it is clear that additional longitudinal studies are required to further investigate the connections between telomeres and hypertension. Of note, establishing statistically significant differences in cross-sectional studies will require large cohorts because telomere length is highly variable among humans. However, smaller sample sizes may be adequate in longitudinal studies designed to evaluate possible differences in telomere attrition rates. These and additional considerations in designing telomere-related epidemiologic studies are thoroughly discussed elsewhere ADDIN EN.CITE Aviv200629529517Aviv, A.Valdes, A. M.Spector, T. D.The Center of Human Development and Aging of the New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA.Human telomere biology: pitfalls of moving from the laboratory to epidemiologyInt J Epidemiol1424-142935200616997848http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16997848 [38].
Mechanistic insight into the role of telomerase and telomeres in hypertension
This section discusses evidence obtained from human and animal studies supporting the notion that alterations in telomerase activity and telomere length may play a role in the pathogenesis of hypertension.
Both endothelial and vascular smooth muscle cells (VSMCs) from human vascular tissues undergo age-dependent telomere attrition ADDIN EN.CITE Chang19953317Chang, E.Harley, C. B.Geron Corp., Menlo Park, CA 94025, USA.Telomere length and replicative aging in human vascular tissuesProc Natl Acad Sci USA11190-1119492AdolescentAdultAged*Cell AgingCell DivisionChild, PreschoolEndothelium, Vascular/*cytologyFemaleHemodynamicsHumanIliac ArteryMaleMiddle AgeStress, MechanicalSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomere/*ultrastructureThoracic Arteries19957479963http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=7479963Okuda20001117Okuda, K.Khan, M. Y.Skurnick, J.Kimura, M.Aviv, H.Aviv, A.Hypertension Research Center, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, 07103-2714, Newark, NJ, USA.Telomere attrition of the human abdominal aorta: relationships with age and atherosclerosisAtherosclerosis391-398152AdolescentAdultAgedAged, 80 and overAging/*geneticsAorta, Abdominal/*ultrastructureArteriosclerosis/*geneticsChildChild, PreschoolFemaleHumanInfantMaleMiddle AgeSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.*TelomereTunica Intima/ultrastructureTunica Media/ultrastructure200010998467http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10998467[39, 40]. Cao et al ADDIN EN.CITE Cao2002292917Cao, Y.Li, H.Mu, F. -T.Ebisui, O.Funder, J. W.Liu, J. -P.Telomerase activation causes vascular smooth muscle cell proliferation in genetic hypertension.FASEB J.96-98162002[41] reported that TERT expression and telomerase activity are induced in the aorta, but not in other tissues, of spontaneously hypertensive rats (SHR) at ages preceding the establishment of hypertension. Although it remains to be established whether this is accompanied by increased telomere length and proliferation within aortic cells in vivo, primary cultures of medial VSMCs obtained from the aorta of SHR displayed increased telomerase activity and telomere length as well as augmented proliferation compared to control VSMCs from Wistar-Kyoto rats (WKY). Moreover, lowering telomerase activity reduced proliferation and induced death in SHR but not in WKY VSMCs ADDIN EN.CITE Cao2002292917Cao, Y.Li, H.Mu, F. -T.Ebisui, O.Funder, J. W.Liu, J. -P.Telomerase activation causes vascular smooth muscle cell proliferation in genetic hypertension.FASEB J.96-98162002[41]. On the other hand, endothelial progenitor cells (EPCs) from hypertensive patients and from SHR and deoxycorticosterone acetate (DOCA)-salt hypertensive rats exhibit reduced telomerase activity and accelerated senescence ADDIN EN.CITE Imanishi200527527517Imanishi, T.Moriwaki, C.Hano, T.Nishio, I.Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan. t-imani@wakayama-med.ac.jpEndothelial progenitor cell senescence is accelerated in both experimental hypertensive rats and patients with essential hypertensionJ HypertensJ Hypertens1831-72310AgedAnimalsBlood Pressure/drug effects*Cell AgingCells, CulturedComparative StudyDesoxycorticosterone/administration & dosageEndothelium, Vascular/pathology/*physiopathologyFemaleHumansHypertension/blood/etiology/*physiopathologyMaleMiddle AgedRatsRats, Inbred SHRRats, Inbred WKYResearch Support, Non-U.S. Gov'tStem Cells/*enzymology/pathologyTelomerase/metabolismbeta-Galactosidase/metabolism2005Oct16148606http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16148606 [42], and angiotensin II-infused hypertensive rats exhibit in EPCs reduced telomerase activity, accelerated senescence and decreased mitogenic activity ADDIN EN.CITE Kobayashi200631231217Kobayashi, K.Imanishi, T.Akasaka, T.Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan.Endothelial progenitor cell differentiation and senescence in an angiotensin II-infusion rat modelHypertens ResHypertens Res449-45529Angiotensin II/*physiologyAngiotensin II Type 1 Receptor Blockers/pharmacologyAnimalsBone Marrow Cells/cytology/drug effects/physiologyCell Aging/*drug effects/physiologyCell Differentiation/*drug effects/physiologyCell Proliferation/drug effectsCells, CulturedEndothelium, Vascular/cytology/*drug effects/physiologyHydralazine/pharmacologyMaleRatsRats, WistarStem Cells/cytology/*drug effects/physiologyTelomerase/physiologyTetrazoles/pharmacologyValine/analogs & derivatives/pharmacologyVasodilator Agents/pharmacology200616940708http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16940708 [43]. Based on these observations, it is tempting to speculate that increased medial VSMC proliferation due to early telomerase activation and increased telomere length may contribute to the initial phases of vascular remodeling associated to hypertension (eg, medial hypertrophy). However, the prolonged exposure to some factors accompanying hypertension may ultimately promote cell senescence, at least in part as a consequence of reduced telomerase activity and accelerated telomere erosion (Fig. 1). Among these factors, inflammation, oxidative stress, and insulin resistance are probably the most important, since they are all linked to hypertension ADDIN EN.CITE Epstein199228428417Epstein, M.Sowers, J. R.Diabetes mellitus and hypertensionHypertension403-4181951992May 1, 1992http://hyper.ahajournals.org/cgi/content/abstract/19/5/403 199428228217National High Blood Pressure Education Program Working Group report on hypertension in diabetesHypertension145-1582321994February 1, 1994http://hyper.ahajournals.org/cgi/content/abstract/23/2/145 Griendling199728528517Griendling, K. K.Alexander, R. W.Oxidative stress and cardiovascular diseaseCirculationCirculation3593-60196101997Gress200028328317Gress, Todd W.Nieto, F. JavierShahar, EyalWofford, Marion R.Brancati, Frederick L.The Atherosclerosis Risk in Communities, StudyHypertension and Antihypertensive Therapy as Risk Factors for Type 2 Diabetes MellitusN Engl J Med905-912342132000March 30, 2000http://content.nejm.org/cgi/content/abstract/342/13/905 10.1056/nejm200003303421301Sowers200428828817Sowers, J. R.Frohlich, E. D.Insulin and insulin resistance: impact on blood pressure and cardiovascular diseaseMed Clin North Am63-828812004Saad200428728717Saad, Mohammed F.Rewers, MarianSelby, JosephHoward, GeorgeJinagouda, SujataFahmi, SalwaZaccaro, DanBergman, Richard N.Savage, Peter J.Haffner, Steven M.Insulin Resistance and Hypertension: The Insulin Resistance Atherosclerosis StudyHypertension1324-13314362004June 1, 2004http://hyper.ahajournals.org/cgi/content/abstract/43/6/1324 10.1161/01.HYP.0000128019.19363.f9Ceriello200428628617Ceriello, AntonioMotz, EnricoIs Oxidative Stress the Pathogenic Mechanism Underlying Insulin Resistance, Diabetes, and Cardiovascular Disease? The Common Soil Hypothesis RevisitedArterioscler Thromb Vasc Biol816-8232452004May 1, 2004http://atvb.ahajournals.org/cgi/content/abstract/24/5/816 10.1161/01.atv.0000122852.22604.78Savoia200629729717Savoia, C.Schiffrin, E. L.Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.Inflammation in hypertensionCurr Opin Nephrol Hypertens152-8152C-Reactive Protein/metabolismCardiovascular Diseases/metabolism/prevention & controlDisease ProgressionFemaleHumansHypertension/epidemiology/*etiology/physiopathologyInflammation/*diagnosis/epidemiologyInflammation Mediators/analysis/*metabolismMalePeroxisome Proliferator-Activated Receptors/*metabolismPrognosisRenin-Angiotensin SystemRisk AssessmentSensitivity and SpecificitySeverity of Illness IndexVascular Resistance/*physiology2006Mar16481882http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16481882 [35, 36, 44-49] and have been proven to accelerate telomere erosion ADDIN EN.CITE Xu200026526517Xu, D.Neville, R.Finkel, T.Laboratory of Molecular Biology, NHLBI, NIH, Bldg 10/7B-15, 10 Center Drive, Bethesda, MD 20892-1650, USA.Homocysteine accelerates endothelial cell senescenceFEBS Lett20-44701Arteriosclerosis/pathologyCatalase/metabolismCell Aging/*drug effectsCells, CulturedEndothelium, Vascular/drug effects/*pathologyHomocysteine/metabolism/*pharmacologyHumansHydrogen Peroxide/metabolismIntercellular Adhesion Molecule-1/biosynthesisPlasminogen Activator Inhibitor 1/biosynthesisTelomere/drug effectsbeta-Galactosidase/metabolism2000Mar 1710722838http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10722838 Breitschopf2001989817Breitschopf, K.Zeiher, A. M.Dimmeler, S.Division of Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanismFEBS Lett21-2549311-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism*AgingAnimalBlotting, WesternCOS CellsCattleCells, CulturedCulture Media, Serum-Free/pharmacologyElectrophoresis, Polyacrylamide GelEndothelium, Vascular/*cytology/*enzymologyEnzyme ActivationEnzyme-Linked Immunosorbent AssayGenes, DominantHumanLipoproteins, LDL/metabolismMitogen-Activated Protein Kinases/metabolismPhosphorylationPlant Proteins/*metabolismPlasmids/metabolismPolymerase Chain ReactionPotassium Channels/*metabolismSupport, Non-U.S. Gov'tTelomerase/genetics/*metabolismTime FactorsTransfectionUmbilical Cord/cytologyp42 MAP Kinase/metabolism200111277998http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11277998Kurz200415215217Kurz, D. J.Decary, S.Hong, Y.Trivier, E.Akhmedov, A.Erusalimsky, J. D.Department of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK.Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cellsJ Cell Sci2417-26117Pt 112004May 115126641http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15126641Gardner200521121117Gardner, Jeffrey P.Li, ShengxuSrinivasan, Sathanur R.Chen, WeiKimura, MasayukiLu, XiaobinBerenson, Gerald S.Aviv, AbrahamRise in insulin resistance is associated with escalated telomere attritionCirculationCirculation2171-2177111172005May 3, 2005http://circ.ahajournals.org/cgi/content/abstract/111/17/2171 10.1161/01.cir.0000163550.70487.0bMatthews200623923917Matthews, C.Gorenne, I.Scott, S.Figg, N.Kirkpatrick, P.Ritchie, A.Goddard, M.Bennett, M.Division of Cardiovascular Medicine, University of Cambridge, Box 110, ACCI, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stressCirc Res156-64992Atherosclerosis/*pathologyBiological Markers/analysis*Cell AgingDNA DamageHumansMuscle, Smooth, Vascular/*pathologyMyocytes, Smooth Muscle/*pathologyOxidants/pharmacologyOxidative StressResearch Support, Non-U.S. Gov'tTelomerase/analysisTelomere/*physiology/ultrastructure2006Jul 2116794190http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16794190 [50-54]. Certainly, additional human and animal studies are required to investigate the possible relationships between telomerase activity/telomere length and insulin resistance, oxidative stress and inflammation markers at different stages of hypertension, both in arterial and circulating cells. It is noteworthy that angiotensin II, which is central to hypertension development ADDIN EN.CITE Mehta200729829817Mehta, P. K.Griendling, K. K.Division of Cardiology, 319 WMB, Emory University, 1639 Pierce Drive, Atlanta, GA 30322, USA.Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular systemAm J Physiol Cell PhysiolC82-9729212007Jan16870827http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16870827 [55], can induce VSMC senescence without reducing telomere length ADDIN EN.CITE Kunieda200629929917Kunieda, T.Minamino, T.Nishi, J.Tateno, K.Oyama, T.Katsuno, T.Miyauchi, H.Orimo, M.Okada, S.Takamura, M.Nagai, T.Kaneko, S.Komuro, I.Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathwayCirculationCirculation953-601149Aging, Premature/*physiopathologyAngiotensin II/*pharmacologyAnimalsAortaApolipoproteins E/deficiency/geneticsAtherosclerosis/*physiopathologyBlood PressureCells, CulturedDisease Models, AnimalGenes, ReporterMiceMice, Inbred C57BLMice, KnockoutMuscle, Smooth, Vascular/drug effects/*growth & developmentTransfection2006Aug 2916908765http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16908765 [56], thus suggesting that telomere-independent mechanisms of vascular senescence might also contribute to hypertension. An inverse relationship has been found between plasma aldosterone concentration and WBC telomere length in normotensive and hypertensive men ADDIN EN.CITE Benetos200530730717Benetos, A.Gardner, J. P.Kimura, M.Labat, C.Nzietchueng, R.Dousset, B.Zannad, F.Lacolley, P.Aviv, A.INSERM Unit 684, University of Nancy, 54511 Nancy-les-Vandoeuvre, France. a.benetos@chu-nancy.frAldosterone and telomere length in white blood cellsJ Gerontol A Biol Sci Med SciJ Gerontol A Biol Sci Med Sci1593-159660AdultAgedAldosterone/*bloodHumans*LeukocytesMaleMiddle AgedTelomere/*ultrastructure2005Dec16424294http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16424294 [57]. Thus, inappropriately high concentrations of this hormone, as those seen in different forms of human hypertension ADDIN EN.CITE Lim200230830817Lim, P. O.Struthers, A. D.MacDonald, T. M.Department of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, Wales, UK. limpo@cf.ac.ukThe neurohormonal natural history of essential hypertension: towards primary or tertiary aldosteronism?J HypertensJ Hypertens11-1520Aldosterone/metabolismAldosterone Synthase/genetics/metabolismDisease ProgressionHumansHyperaldosteronism/epidemiology/*etiology/*metabolismHypertension/*etiology/*metabolismNeurotransmitter Agents/*metabolismPolymorphism, Genetic/physiologyPrevalenceRenin/metabolismRenin-Angiotensin System/physiologySeverity of Illness IndexSympathetic Nervous System/physiopathologyVascular Resistance/physiology2002Jan11791020http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11791020 [58], may be linked to a higher rate of telomere attrition and perhaps increased biological aging in these patients.
Supporting the notion that telomere dysfunction and hypertension are causally linked, Perez-Rivero et al ADDIN EN.CITE Perez-Rivero200625725717Perez-Rivero, G.Ruiz-Torres, M. P.Rivas-Elena, J. V.Jerkic, M.Diez-Marques, M. L.Lopez-Novoa, J. M.Blasco, M. A.Rodriguez-Puyol, D.Research Unit, Principe de Asturias Hospital, Alcala de Henares, Madrid, Spain.Mice deficient in telomerase activity develop hypertension because of an excess of endothelin productionCirculationCirculation309-1711442006Jul 2516831983http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16831983 [29] found that first and third generation of TERC-deficient mice exhibit higher blood and urinary levels of the endothelium-derived vasoconstrictor peptide endothelin-1 (ET-1) and develop hypertension. Since no differences in the expression of the precursor pre-pro-ET-1 were detected in aorta and renal cortex of TERC-null mice, it was postulated that increased levels of circulating ET-1 may be due to increased expression of the endothelin-converting enzime (ECE-1), which converts pre-pro-ET-1 into biologically active ET-1. Indeed, ECE-1 mRNA expression was significantly higher in TERC-deficient mice than in wild-type counterparts, and ECE-1 promoter activity was increased in murine embrionary fibroblasts obtained from TERC-deficient mice. These cells also displayed enhanced production of reactive oxygen species and their treatment with antioxidants, such as catalase and N-acetilcysteine, reduced ECE-1 promoter activity. These findings suggest a causal link between the synthesis of reactive oxygen species and ET-1 levels and support a role of oxidative stress in telomere erosion in hypertension. It was also shown that expression of a TRF2 dominant negative mutant which destroys telomere structure induces in endothelial cells a senescent phenotype and diminished endothelial nitric oxide synthase activity ADDIN EN.CITE Minamino2002272717Minamino, T.Miyauchi, H.Yoshida, T.Ishida, Y.Yoshida; H.Komuro, I.Endothelial cell senescence in human atherosclerosis. Role of telomere in endothelial dysfunction.CirculationCirculation1541-15441052002[59]. Collectively, these observations suggest that telomere dysfunction may induce premature senescence and modify the phenotypic characteristics of vascular cells in a way that favors development of hypertension (e. g., altering the production of vasomodulators) ADDIN EN.CITE Perez-Rivero200625725717Perez-Rivero, G.Ruiz-Torres, M. P.Rivas-Elena, J. V.Jerkic, M.Diez-Marques, M. L.Lopez-Novoa, J. M.Blasco, M. A.Rodriguez-Puyol, D.Research Unit, Principe de Asturias Hospital, Alcala de Henares, Madrid, Spain.Mice deficient in telomerase activity develop hypertension because of an excess of endothelin productionCirculationCirculation309-1711442006Jul 2516831983http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16831983 [29].
Telomeres, telomerase and target organ damage in hypertension
Human and animal studies that have demonstrated relationships of telomere dysfunction with target organ damage in hypertension are summarized in Fig. 2. Changes in the composition of cardiac tissue develop in arterial hypertension and lead to structural remodeling of the myocardium. Structural remodeling is the consequence of a number of pathologic processes, mediated by mechanical, neurohormonal and cytokine routes, occurring in the cardiomyocyte and the noncardiomyocyte compartments of the heart. It is classically admitted that cardiomyocyte hypertrophy leading to left-ventricular hypertrophy provides the adaptive response of the heart to pressure overload in an attempt to normalize systolic wall stress. However, recent experimental and clinical studies have also provided evidence for stimulation of cardiomyocyte apoptosis leading to either cell death or dysfunction in the hypertensive heart ADDIN EN.CITE Gonzlez200630030017Gonzlez, A.Ravassa, S.Lpez, B.Loperena, I.Querejeta, R.Dez, J.Apoptosis in hypertensive heart disease: a clinical approachCurrent Opinion in Cardiology288-2942142006[60]. Furthermore, the available findings suggest that cardiomyocyte apoptosis precedes the impairment in ventricular function and its exacerbation accompanies the development of heart failure in hypertensive patients with cardiac hypertrophy.
The role of telomerase in cardiac pathophysiology is highlighted by studies in late-generation Terc-null mice with critically short telomeres, which exhibit ventricular dilation, thinning of the myocardium, cardiac dysfunction and sudden death, as well as reduced proliferation and increased apoptosis of cardiomyocytes ADDIN EN.CITE Leri2003131317Leri, A.Franco, S.Zacheo, A.Barlucchi, L.Chimenti, S.Limana, F.Nadal-Ginard, B.Kajstura, J.Anversa, P.Blasco, M. A.Department of Medicine, Cardiovascular Research Institute, New York Medical College, Valhalla, NY 10595, USA.Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulationEmbo J131-13922AnimalCells, CulturedDisease Models, AnimalGene Expression Regulation*Genes, p53Heart/*physiology/physiopathologyHeart Failure, Congestive/*geneticsHumanMiceMice, KnockoutMuscle Cells/cytology/physiologyProtein p53/*geneticsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomerase/*deficiency/*genetics/metabolismTelomere/*genetics/ultrastructureVasodilation/*genetics200312505991http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12505991[27]. Challenging the classical dogma considering the adult heart as a postmitotic tissue, evidence is mounting suggesting the presence of telomerase-expressing multipotent cardiac stem cells in adult myocardium, which may support regeneration of the damaged heart ADDIN EN.CITE Beltrami200313113117Beltrami, 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.Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.Adult cardiac stem cells are multipotent and support myocardial regenerationCell763-7761146AnimalBiological MarkersBlood Vessels/cytology/growth & developmentCell Differentiation/*physiologyCell Lineage/physiologyCells, CulturedClone Cells/cytology/metabolismEndothelium, Vascular/cytology/metabolismFemaleHeart/*physiologyMultipotent Stem Cells/*cytology/metabolism/transplantationMyocardial Infarction/therapyMyocardium/*cytology/metabolismMyocytes, Cardiac/*cytology/metabolismMyocytes, Smooth Muscle/cytology/metabolismProto-Oncogene Protein c-kit/genetics/metabolismRatsRats, Inbred F344Regeneration/*physiologySupport, U.S. Gov't, P.H.S.2003Sep 1914505575http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14505575Oh200313613617Oh, H.Bradfute, S. B.Gallardo, T. D.Nakamura, T.Gaussin, V.Mishina, Y.Pocius, J.Michael, L. H.Behringer, R. R.Garry, D. J.Entman, M. L.Schneider, M. D.Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarctionProc Natl Acad Sci U S A12313-12318100AnimalsCell DifferentiationCell FusionCell MovementCell SeparationGene ExpressionGenes, ReporterGenes, StructuralIn VitroMiceMice, Inbred C57BLMyoblasts, Cardiac/metabolism/*pathologyMyocardial Infarction/genetics/*pathologySupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Transcription Factors/genetics200314530411http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14530411Urbanek2003787817Urbanek, K.Quaini, F.Tasca, G.Torella, D.Castaldo, C.Nadal-Ginard, B.Leri, A.Kajstura, J.Quaini, E.Anversa, P.Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.Intense myocyte formation from cardiac stem cells in human cardiac hypertrophyProc Natl Acad Sci U S A10440-10445100200312928492http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12928492Urbanek200524024017Urbanek, KonradTorella, DanieleSheikh, FarooqDe Angelis, AntonellaNurzynska, DariaSilvestri, FurioBeltrami, C. AlbertoBussani, RossanaBeltrami, Antonio P.Quaini, FedericoBolli, RobertoLeri, AnnarosaKajstura, JanAnversa, PieroMyocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failurePNAS8692-8697102242005June 14, 2005http://www.pnas.org/cgi/content/abstract/102/24/8692 10.1073/pnas.0500169102[61-64]. Moreover, new myocyte formation during aortic valve stenosis-induced cardiac hypertrophy may arise from the differentiation of telomerase-positive cardiac stem cells ADDIN EN.CITE Urbanek2003787817Urbanek, K.Quaini, F.Tasca, G.Torella, D.Castaldo, C.Nadal-Ginard, B.Leri, A.Kajstura, J.Quaini, E.Anversa, P.Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.Intense myocyte formation from cardiac stem cells in human cardiac hypertrophyProc Natl Acad Sci U S A10440-10445100200312928492http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12928492[63]. Remarkably, cardiac-specific TERT-transgenic mice exhibit early cardiomyocyte hyperplasia and late-onset myocardial hypertrophy ADDIN EN.CITE Oh2001797917Oh, H.Taffet, G. E.Youker, K. A.Entman, M. L.Overbeek, P. A.Michael, L. H.Schneider, M. D.Center for Cardiovascular Development, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survivalProc Natl Acad Sci U S A10308-1031398AnimalApoptosis/physiologyBase SequenceCardiomegaly/enzymology/etiologyCell Division/physiologyCell Size/physiologyCell Survival/physiologyCells, CulturedDNA Primers/geneticsGene Expression Regulation, DevelopmentalHumanMiceMice, TransgenicMyocardium/*cytology/*enzymologyRatsSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomerase/genetics/*physiologyTelomere/ultrastructure200111517337http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11517337[65].
Taken together, the aforementioned studies suggest a role of telomerase activation in adaptative changes of cardiomyocytes in the hypertensive heart. However, telomere dysfunction may also contribute to maladaptive cardiac hypertrophy and ensuing heart failure. First, telomere attrition has been detected in the heart of patients with cardiac hypertrophy consecutive to aortic stenosis with a mean duration of three years, in spite of increased telomerase activity ADDIN EN.CITE Urbanek2003787817Urbanek, K.Quaini, F.Tasca, G.Torella, D.Castaldo, C.Nadal-Ginard, B.Leri, A.Kajstura, J.Quaini, E.Anversa, P.Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.Intense myocyte formation from cardiac stem cells in human cardiac hypertrophyProc Natl Acad Sci U S A10440-10445100200312928492http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12928492[63]. Likewise, augmented telomerase activity in the aged diseased human heart does not prevent telomere attrition ADDIN EN.CITE Chimenti2003777717Chimenti, 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.Cardiovascular Research Institute, Department of Medicine, New York Medical College, Vosburgh Pavilion, Room 302, Valhalla, NY 10595, USA.Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failureCirc Res604-61393AgedAged, 80 and overBiopsyCardiomyopathy, Congestive/pathology*Cell AgingCell Cycle Proteins/metabolismCell DeathComparative StudyFemaleHeart Failure, Congestive/*pathologyHumanMaleMicroscopy, ConfocalMitotic IndexMyocardium/metabolism/*pathologyMyocytes, Cardiac/metabolism/*pathologyProtein p16/metabolismSupport, U.S. Gov't, P.H.S.Telomerase/metabolism200312958145http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=12958145[66]. Second, both in a murine model of cardiac hypertrophy and heart failure induced by severe mechanical overload for 1 week and in patients experiencing end-stage heart failure, cardiac tissue exhibits diminished levels of the telomere repeat binding factor 2 (TRF2), shortened telomeres and activated Chk2 ADDIN EN.CITE Oh2003575717Oh, HidemasaWang, Sam C.Prahash, ArunSano, MotoakiMoravec, Christine S.Taffet, George E.Michael, Lloyd H.Youker, Keith A.Entman, Mark L.Schneider, Michael D.Telomere attrition and Chk2 activation in human heart failurePNASPNAS5378-53831002003http://www.pnas.org/cgi/content/abstract/100/9/5378[67]. Similarly, TRF2 inactivation in cultured cardiomyocytes rapidly induced telomere shortening, activation of Chk2 and apoptosis, and exogenous TRF2 protected cardiomyocytes from oxidative stress. The in vivo responses to mechanical overload were inhibited by ectopically expressing TERT at levels normal for the embryonic heart, which also reduced replacement fibrosis and preserved systolic function. In the absence of heart failure, however, the hypertrophied heart did not display telomere attrition and TRF2 donwnregulation ADDIN EN.CITE Oh2003575717Oh, HidemasaWang, Sam C.Prahash, ArunSano, MotoakiMoravec, Christine S.Taffet, George E.Michael, Lloyd H.Youker, Keith A.Entman, Mark L.Schneider, Michael D.Telomere attrition and Chk2 activation in human heart failurePNASPNAS5378-53831002003http://www.pnas.org/cgi/content/abstract/100/9/5378[67].
Oxidative stress plays an important role in cardiac hypertrophy and its transition to heart failure ADDIN EN.CITE Takimoto200727927917Takimoto, EikiKass, David A.Role of Oxidative Stress in Cardiac Hypertrophy and RemodelingHypertension241-2484922007February 1, 2007http://hyper.ahajournals.org 10.1161/01.HYP.0000254415.31362.a7Dhalla199628028017Dhalla, A. K.Hill, M. F.Singal, P. K.Role of oxidative stress in transition of hypertrophy to heart failureJ Am Coll Cardiol506-5142821996August 1, 1996http://content.onlinejacc.org/cgi/content/abstract/28/2/506 [68, 69], and accelerates telomere erosion ADDIN EN.CITE Xu200026526517Xu, D.Neville, R.Finkel, T.Laboratory of Molecular Biology, NHLBI, NIH, Bldg 10/7B-15, 10 Center Drive, Bethesda, MD 20892-1650, USA.Homocysteine accelerates endothelial cell senescenceFEBS Lett20-44701Arteriosclerosis/pathologyCatalase/metabolismCell Aging/*drug effectsCells, CulturedEndothelium, Vascular/drug effects/*pathologyHomocysteine/metabolism/*pharmacologyHumansHydrogen Peroxide/metabolismIntercellular Adhesion Molecule-1/biosynthesisPlasminogen Activator Inhibitor 1/biosynthesisTelomere/drug effectsbeta-Galactosidase/metabolism2000Mar 1710722838http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10722838 Breitschopf2001989817Breitschopf, K.Zeiher, A. M.Dimmeler, S.Division of Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt, Germany.Pro-atherogenic factors induce telomerase inactivation in endothelial cells through an Akt-dependent mechanismFEBS Lett21-2549311-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolism*AgingAnimalBlotting, WesternCOS CellsCattleCells, CulturedCulture Media, Serum-Free/pharmacologyElectrophoresis, Polyacrylamide GelEndothelium, Vascular/*cytology/*enzymologyEnzyme ActivationEnzyme-Linked Immunosorbent AssayGenes, DominantHumanLipoproteins, LDL/metabolismMitogen-Activated Protein Kinases/metabolismPhosphorylationPlant Proteins/*metabolismPlasmids/metabolismPolymerase Chain ReactionPotassium Channels/*metabolismSupport, Non-U.S. Gov'tTelomerase/genetics/*metabolismTime FactorsTransfectionUmbilical Cord/cytologyp42 MAP Kinase/metabolism200111277998http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11277998Kurz200415215217Kurz, D. J.Decary, S.Hong, Y.Trivier, E.Akhmedov, A.Erusalimsky, J. D.Department of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK.Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cellsJ Cell Sci2417-26117Pt 112004May 115126641http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15126641Matthews200623923917Matthews, C.Gorenne, I.Scott, S.Figg, N.Kirkpatrick, P.Ritchie, A.Goddard, M.Bennett, M.Division of Cardiovascular Medicine, University of Cambridge, Box 110, ACCI, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK.Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: effects of telomerase and oxidative stressCirc Res156-64992Atherosclerosis/*pathologyBiological Markers/analysis*Cell AgingDNA DamageHumansMuscle, Smooth, Vascular/*pathologyMyocytes, Smooth Muscle/*pathologyOxidants/pharmacologyOxidative StressResearch Support, Non-U.S. Gov'tTelomerase/analysisTelomere/*physiology/ultrastructure2006Jul 2116794190http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16794190 [50-52, 54]. In line with these observations, cardiac stem cells and cardiomyocytes from mice with streptozotocin-induced diabetes exhibit shorter telomeres associated to oxidative stress ADDIN EN.CITE Rota200629229217Rota, MarcelloLeCapitaine, NicoleHosoda, ToruBoni, AlessandroDe Angelis, AntonellaPadin-Iruegas, Maria ElenaEsposito, GraziaVitale, SerenaUrbanek, KonradCasarsa, ClaudiaGiorgio, MarcoLuscher, Thomas F.Pelicci, Pier GiuseppeAnversa, PieroLeri, AnnarosaKajstura, JanDiabetes Promotes Cardiac Stem Cell Aging and Heart Failure, Which Are Prevented by Deletion of the p66shc GeneCirc Res42-529912006July 7, 2006http://circres.ahajournals.org/cgi/content/abstract/99/1/42 10.1161/01.res.0000231289.63468.08[70]. Telomere attrition was not observed in cardiomyocytes from diabetic p66shc-deficient mice with attenuated production of reactive oxygen species ADDIN EN.CITE Rota200629229217Rota, MarcelloLeCapitaine, NicoleHosoda, ToruBoni, AlessandroDe Angelis, AntonellaPadin-Iruegas, Maria ElenaEsposito, GraziaVitale, SerenaUrbanek, KonradCasarsa, ClaudiaGiorgio, MarcoLuscher, Thomas F.Pelicci, Pier GiuseppeAnversa, PieroLeri, AnnarosaKajstura, JanDiabetes Promotes Cardiac Stem Cell Aging and Heart Failure, Which Are Prevented by Deletion of the p66shc GeneCirc Res42-529912006July 7, 2006http://circres.ahajournals.org/cgi/content/abstract/99/1/42 10.1161/01.res.0000231289.63468.08Migliaccio199929329317Migliaccio, EnricaGiorgio, MarcoMele, SimonettaPelicci, GiulianaReboldi, PaoloPandolfi, Pier PaoloLanfrancone, LuisaPelicci, Pier GiuseppeThe p66shc adaptor protein controls oxidative stress response and life span in mammalsNature309-31340267591999http://dx.doi.org/10.1038/46311http://www.nature.com/nature/journal/v402/n6759/suppinfo/402309a0_S1.html Giorgio200529429417Giorgio, MarcoMigliaccio, EnricaOrsini, FrancescaPaolucci, DemisMoroni, MaurizioContursi, CristinaPelliccia, GiovanniLuzi, LucillaMinucci, SaverioMarcaccio, MassimoPinton, PaoloRizzuto, RosarioBernardi, PaoloPaolucci, FrancescoPelicci, Pier GiuseppeElectron Transfer between Cytochrome c and p66Shc Generates Reactive Oxygen Species that Trigger Mitochondrial ApoptosisCell221-23312222005http://www.sciencedirect.com/science/article/B6WSN-4GRH1R2-C/2/c2eeca7e02ba4f65dbadc6c1070a1fce [70-72], thus suggesting a link between telomere shortening in the heart, oxidative stress and diabetes.
It is not yet known whether aging is inevitably accompanied by a decline in renal function or how rapidly it might happen. However, it is accepted that morbid conditions, such as hypertension, facilitate and accelerate age-related renal deterioration. A role for telomeres length as one of the molecular mechanisms regulating such a relationship has been proposed ADDIN EN.CITE Buemi200530130117Buemi, M.Nostro, L.Aloisi, C.Cosentini, V.Criseo, M.Frisina, N.Department of Internal Medicine, University of Messina, Messina, Italy. buemim@unime.itKidney aging: from phenotype to geneticsRejuvenation Res101-982AgedAging/*geneticsHumansKidney/pathology/*physiopathologyKidney Failure/*genetics/*physiopathologyPhenotype2005Summer15929718http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15929718 [73]. Indeed, the analysis of surgical samples from 24 human kidneys has revealed that telomeres shorten in the aging kidney, particularly in renal cortex ADDIN EN.CITE Melk200030930917Melk, A.Ramassar, V.Helms, L. M.Moore, R.Rayner, D.Solez, K.Halloran, P. F.Department of Surgery, University of Alberta, Edmonton, Canada.Telomere shortening in kidneys with ageJ Am Soc NephrolJ Am Soc Nephrol444-45311AdultAgedAged, 80 and overAging/*physiologyChildChild, PreschoolDNA/metabolismFemaleGlomerular Filtration RateHumansInfantInfant, NewbornKidney/*physiologyKidney Cortex/metabolism/physiologyKidney Medulla/metabolism/physiologyMaleMiddle AgedRegression AnalysisTelomere/*genetics2000Mar10703668http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10703668 [74]. In this conceptual framework, Hamet et al ADDIN EN.CITE Hamet200130230217Hamet, P.Thorin-Trescases, N.Moreau, P.Dumas, P.Tea, B. S.deBlois, D.Kren, V.Pravenec, M.Kunes, J.Sun, Y.Tremblay, J.Centre de recherche, Centre hospitalier de l'Universite de Montreal, Montreal, Quebec, Canada.Workshop: excess growth and apoptosis: is hypertension a case of accelerated aging of cardiovascular cells?Hypertension760-6372 Part 2AnimalsAnimals, NewbornApoptosis/*geneticsBody WeightCell Aging/geneticsCrosses, GeneticDNA/isolation & purification/metabolismDNA FragmentationFemaleHeart/embryology/growth & developmentHypertension/*etiologyKidney/embryology/growth & development/pathologyMaleMyocardium/*pathologyOrgan SizePolymorphism, Restriction Fragment LengthRatsRats, Inbred BNRats, Inbred SHRRats, Inbred WKYTelomere/pathologyThymidine/administration & dosageTritium2001Feb11230370http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11230370 [75] found shorter telomeres in kidneys from SHR compared with nomotensive rats at all ages examined. Since the half-life of cells in the kidney is actually decreased by ~50% in SHR compared with normotensive rats ADDIN EN.CITE Thorin-Trescases200130330317Thorin-Trescases, N.deBlois, D.Hamet, P.Research Centre, University of Montreal Health Centre-Hotel Dieu, University of Montreal, Montreal, Quebec, Canada.Evidence of an altered in vivo vascular cell turnover in spontaneously hypertensive rats and its modulation by long-term antihypertensive treatmentJ Cardiovasc Pharmacol764-74385Age FactorsAgingAnimalsAnimals, NewbornAntihypertensive Agents/*therapeutic useAorta/*drug effects/metabolism/physiopathologyBlood Pressure/drug effectsBody Weight/drug effectsCarbon RadioisotopesCell DeathDNA/analysis/biosynthesisDNA FragmentationHypertension/drug therapy/*physiopathologyHypertrophy/prevention & controlOrgan Size/drug effectsRatsRats, Inbred SHRRats, Inbred WKYThymidine/*analogs & derivatives/metabolismTime FactorsTritium2001Nov11602823http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11602823 [76], it is possible that the hypertensive kidney is characterized by accelerated senescence with increased cell turnover. The potential pathophysiological relevance of this possibility is supported by two facts: (1) subjects with essential hypertension are at increased risk for a particular form of chronic kidney disease (e.g. nephroangiosclerosis) ADDIN EN.CITE Rosario200630530517Rosario, R. F.Wesson, D. E.Departments of Internal Medicine and Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430, USA. Rey.Rosario@ttuhsc.eduPrimary hypertension and nephropathyCurr Opin Nephrol Hypertens130-4152Albuminuria/etiology/physiopathologyCardiovascular Diseases/epidemiology/*etiology/physiopathologyChronic DiseaseDisease ProgressionFemaleFollow-Up StudiesGlomerular Filtration RateHumansHypertension/*complications/diagnosisIncidenceKidney Failure, Chronic/epidemiology/*etiology/physiopathologyMaleNitric Oxide/metabolismProteinuria/etiology/physiopathologyRisk AssessmentSeverity of Illness Index2006Mar16481878http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16481878 [77], and (2) the kidney of patients with nephroangiosclerosis exhibits pathological features similar to the microscopic changes seen in the kidney of normotensive elderly subjects ADDIN EN.CITE Ono199730630617Ono, H.Ono, Y.Department of Internal Medicine, Dokkyo University School of Medicine, Tochigi, Japan.Nephrosclerosis and hypertensionMed Clin North Am1273-88816AnimalsHemodynamic ProcessesHumansHypertension/classification/*complicationsNephrosclerosis/*complications/*pathology1997Nov9356598http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=9356598 [78].
It is well established that hypertensive subjects are at higher risk for atherosclerosis. However, not all hypertensive patients ultimately manifest atherosclerotic complications. The reasons for this interindividual diversity are unknown but may reflect differences in environmental and/or genetic factors, such as oxidative stress, inflammation, and other molecular and cellular mechanisms that are related to aging. A number of data suggest that individuals with shorter telomeres in leukocytes have a higher prevalence of atherosclerotic lesions and elevated risk of cardiovascular events related to atherosclerosis ADDIN EN.CITE Samani20017717Samani, N. J.Boultby, R.Butler, R.Thompson, J. R.Goodall, A. H.Telomere shortening in atherosclerosisLancetLancet472-473358AdultAgedCase-Control StudiesCell AgingCoronary Arteriosclerosis/*genetics/pathologyFemaleHumanLeukocytes/ultrastructureMaleMiddle AgeSupport, Non-U.S. Gov'tTelomere/*ultrastructure200111513915http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11513915[79]. HYPERLINK "http://hyper.ahajournals.org/cgi/external_ref?access_num=10.1016/S0140-6736%2801%2905633-1&link_type=DOI" In this regard, it was shown that telomere length in WBCs is shorter in hypertensive men with carotid artery plaques versus hypertensive men without plaques ADDIN EN.CITE Benetos200420320317Benetos, A.Gardner, J. P.Zureik, M.Labat, C.Xiaobin, L.Adamopoulos, C.Temmar, M.Bean, K. E.Thomas, F.Aviv, A.Centre d'Investigations Preventives et Cliniques, 6/14 rue la Perouse, 75116 Paris, France. benetos@ipc.asso.frShort telomeres are associated with increased carotid atherosclerosis in hypertensive subjectsHypertension182-5432Carotid Artery Diseases/*etiology/genetics/ultrasonographyHumanHypertension/*complicationsMaleMiddle AgedSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Telomere/*chemistry2004Feb14732735http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14732735[80]. Multivariate analysis showed that in addition to age, telomere length is a significant predictor of the presence of carotid artery plaques. The findings from this study suggest that in the presence of chronic hypertension, which is a major risk factor for atherosclerosis, shorter telomere length in WBCs is associated with an increased predilection to carotid artery atherosclerosis. The possible role of telomere dysfunction on atherosclerosis and how cardiovascular risk factors affect telomerase activity and telomere length is comprehensively discussed elsewhere ADDIN EN.CITE Fuster200628928917Fuster, Jose J.Andres, VicenteTelomere Biology and Cardiovascular DiseaseCirc Res1167-118099112006November 24, 2006http://circres.ahajournals.org/cgi/content/abstract/99/11/1167 10.1161/01.res.0000251281.00845.18[16].
Conclusions and perspectives
Telomere biology is emerging as an important issue in the pathogenesis of hypertension. Telomere length is highly variable among individuals of the same age and is determined by both genetic and environmental factors. In the SHR model, telomerase activation was observed in the aorta before the onset of hypertension, and telomeres were longer in primary cultures of aortic medial VSMCs obtained from these animals compared to cells from WKY controls. However, several studies showed a connection between established hypertension and low telomerase activity and/or short telomeres: (1) compared to normotensive subjects, hypertensive patients exhibit shorter telomeres in WBCs; (2) lower telomerase activity was detected in EPCs from hypertensive rats and patients with essential hypertension, which may contribute to premature cell senescence; and (3) TERC-null mice exhibit augmented expression of the vasoconstrictor peptide ET-1 and develop hypertension. Thus, increased arterial telomerase activity in pre-hypertensive stages may contribute to the onset of pathological vascular remodeling in SHR by inducing hyperplastic growth of arterial VSMCs. Whether these alterations also occur in humans is unknown. Based on the findings in WBCs and EPCs, it can be suggested that prolonged exposure to risk factors which are frequently associated to high blood pressure and known to inhibit telomerase activity and accelerate telomere shortening (e.g. oxidative stress and insulin resistance) may ultimately provoke VSMC senescence and favour disease progression (e.g. by increasing arterial stiffness or inducing the synthesis of vasoconstrictor molecules, such as ET-1) (Fig. 1). Therefore, it is of utmost importance to investigate whether telomerase activity and/or telomere length are also altered in arterial cells from hypertensive patients and experimental animals.
Regarding target organ damage (Fig. 2), both telomerase activation and telomere attrition have been observed in hypertension-related heart disease: (1) telomerase activity is necessary for cardiac stem cell proliferation and thus may support new cardiomyocyte formation during cardiac hypertrophy; and (2) telomere shortening may contribute to the transition from maladaptive cardiac hypertrophy to heart failure. In support of this notion, telomere exhaustion occurs in cardiac hypertrophy consecutive to aortic stenosis and in the aged diseased heart, in spite of the presence of telomerase activity. Moreover, mechanical injury in the heart downregulates TRF2, shortens telomeres and activates DNA damage-induced apoptosis in cardiac tissue. Like in the vascular wall, oxidative stress appears to contribute significantly to telomere erosion in the diseased heart. On the other hand, accelerated telomere attrition of cortex cells may be one of the factors involved in accelerated aging of the kidney in hypertension and this, in turn, may facilitate the development of nephroangiosclerosis.
As our knowledge on telomeres and cardiovascular disease grows, the challenge will be to ascertain whether all this information might translate into clinical applications. In particular, whether targeting the telomere and associated proteins is a suitable therapeutic strategy for the treatment of hypertension and related target organ damage is unknown at present. Of interest, it has been reported that the rate of senescence and telomerase activity in EPCs were significantly higher and lower, respectively, in rats treated with angiotensin II alone than in rats treated with the angiotensin II plus the AT1 receptor blocker valsartan ADDIN EN.CITE Kobayashi200631231217Kobayashi, K.Imanishi, T.Akasaka, T.Department of Cardiovascular Medicine, Wakayama Medical University, Wakayama, Japan.Endothelial progenitor cell differentiation and senescence in an angiotensin II-infusion rat modelHypertens ResHypertens Res449-45529Angiotensin II/*physiologyAngiotensin II Type 1 Receptor Blockers/pharmacologyAnimalsBone Marrow Cells/cytology/drug effects/physiologyCell Aging/*drug effects/physiologyCell Differentiation/*drug effects/physiologyCell Proliferation/drug effectsCells, CulturedEndothelium, Vascular/cytology/*drug effects/physiologyHydralazine/pharmacologyMaleRatsRats, WistarStem Cells/cytology/*drug effects/physiologyTelomerase/physiologyTetrazoles/pharmacologyValine/analogs & derivatives/pharmacologyVasodilator Agents/pharmacology200616940708http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16940708 [43]. Since these two parameters were unchanged in rats receiving angiotensin II plus hydralazine, it can be hypothesized that AT1 receptor blockade may have specific beneficial effects on telomere dysfunction in hypertension. On the other hand, it has been shown that thiazolidinediones, which are anti-diabetic agents that can reduce restenosis ADDIN EN.CITE Marx200531031017Marx, N.Wohrle, J.Nusser, T.Walcher, D.Rinker, A.Hombach, V.Koenig, W.Hoher, M.Department of Internal Medicine II, Cardiology, University of Ulm, Ulm, Germany.Pioglitazone reduces neointima volume after coronary stent implantation: a randomized, placebo-controlled, double-blind trial in nondiabetic patientsCirculationCirculation2792-2798112Administration, OralAgedAngioplasty, Transluminal, Percutaneous Coronary/*adverse effectsAspirin/administration & dosage/therapeutic useBiological Markers/bloodCoronary Disease/surgeryCoronary Restenosis/*prevention & controlDouble-Blind MethodFemaleHumansHypoglycemic Agents/therapeutic useInflammation/blood/prevention & controlInjections, IntravenousMaleMiddle AgedPlacebosThiazolidinediones/*therapeutic useTunica Intima/drug effects/*pathology200516246947http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16246947 [81], cause VSMC growth arrest via TERT inhibition ADDIN EN.CITE Ogawa200623123117Ogawa, DaisukeNomiyama, TakashiNakamachi, TakafumiHeywood, Elizabeth B.Stone, Jeffrey F.Berger, Joel P.Law, Ronald E.Bruemmer, DennisActivation of peroxisome proliferator-activated receptor gamma suppresses telomerase activity in vascular smooth muscle cellsCirc Rese50-599872006April 14, 2006http://circres.ahajournals.org/cgi/content/abstract/98/7/e50 10.1161/01.RES.0000218271.93076.c3[82]. Very recently, Brouilette et al. ADDIN EN.CITE Brouilette200731131117Brouilette, S. W.Moore, J. S.McMahon, A. D.Thompson, J. R.Ford, I.Shepherd, J.Packard, C. J.Samani, N. J.Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control studyLancetLancet107-114369Aging/physiologyBlood Pressure/drug effectsCase-Control StudiesCholesterol/bloodCoronary Disease/*etiology/prevention & controlFollow-Up StudiesHumansHydroxymethylglutaryl-CoA Reductase Inhibitors/*therapeutic useMaleMiddle AgedPolymerase Chain ReactionPravastatin/*therapeutic useRisk FactorsScotlandTelomere/*drug effects/genetics/physiology200717223473http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17223473 [83] reported that the risk of developing coronary artery disease was increased by about two-fold in individuals with shorter WBC telomere length, and pravastatin completely attenuated this telomere-related risk. Thus, mean leukocyte telomere length could identify individuals who would benefit most from statin treatment. Likewise, recent data suggest that shorter telomere length in hypertension may be one of the factors that explain why some hypertensive patients are more prone than others to developing atherosclerotic lesions. Whether 'telomerization' strategies may find therapeutic application to prevent or ameliorate target organ damage in hypertension remains to be explored.
In conclusion, more basic research is needed to shed light on the relationships between telomere pathobiology and hypertension. Because most studies have focused so far on telomerase, it is necessary to explore the role in hypertension of additional telomere-associated proteins. Research in this field would benefit from the generation of genetically-modified mice exhibiting tissue-specific alterations in telomere-associated proteins. Furthermore, large cross-sectional and longitudinal population-based studies are required to address two unresolved questions: (1) does short telomere length at birth predispose to hypertension and related disease?; and (2) given that an accelerated rate of telomere shortening may be expected from the chronic exposure to factors frequently associated to high blood pressure, is exaggerated telomere exhaustion a surrogate marker of hypertension and related diseases? If so, measuring telomere attrition rates may become a useful tool to identify hypertensive patients who are more prone to experience target organ damage.
Acknowledgements
We thank Mara J. Andrs-Manzano for helping with the preparation of figures.
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Figure 1. Hypothetical model of telomere and telomerase alterations in different stages of hypertension. The schematic represents a working model based on a limited number of animal and human studies. Early telomerase activation and telomere lengthening within the artery wall may promote pathological vascular remodeling before the establishment of hypertension in the SHR model. At later stages, and due to the chronic action of risk factors which are frequently associated to high blood pressure and known to inhibit telomerase activity, accelerated telomere exhaustion may cause phenotypic alterations that contribute to hypertension development (e.g. cell senescence, increased arterial stiffness, altered synthesis of vasomodulators). Validation of this model requires human studies to assess whether pre-hypertension stages are associated with arterial telomerase activation and telomere lengthening, as has been shown in the SHR model. Moreover, it needs to be determined if telomere attrition and ensuing cell senescence occur within the artery wall in hypertensive patients and animals. Reference nos. are shown. DOCA: deoxycorticosterone acetate; ECs: endothelial cells; eNOS: endothelial nitric oxide synthase; EPCs: endothelial progenitor cells; ET-1: endothelin 1; SHR: spontaneously hypertensive rat; TERC: telomerase RNA component; TRF2: telomere repeat-binding factor 2; VSMC: vascular smooth muscle cell; WBC: white blood cell.
Figure 2. Human and animal studies linking telomere dysfunction to target organ damage in hypertension. Reference nos. are shown. TERC: Telomerase RNA component; TERT: Telomerase reverse transcriptase component; TRF2: Telomere repeat binding factor 2; WBC: white blood cell.
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