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Genetic and Cellular Aspects of Arterial Stiffness

  • Athanase BenetosEmail author
  • Abraham Aviv
  • Patrick Lacolley
  • Michel E. Safar
  • Véronique Regnault
Chapter

Abstract

Increases in arterial stiffness and pulse pressure are typical features of the arterial stiffness during aging and are associated with increased risk of cardiovascular complications. Cellular and molecular determinants of arterial stiffness have not been completely elucidated. Clinically, the carotid-femoral pulse wave velocity (PWV) is the gold standard parameter of arterial stiffness. A recent genome-wide scan of the Framingham Heart Study population has shown that arterial stiffness and mean and pulsatile components of blood pressure are heritable and map to separate the genetic loci in humans, suggesting that distinct genes may modulate these two phenotypes. This chapter details the recent knowledge on the influence of genetic determinants and telomere length on the development of age-related phenotypes. Recent genetic studies have revealed specific genes contributing to arterial stiffening. Available data on genome-wide association (GWA) have been initiated on PWV and have identified common genetic variation in specific loci or single-nucleotide polymorphisms (SNP) significantly associated with PWV. Telomere length at birth is strongly determined genetically and is the main determinant of leukocytes’ telomere length (LTL) later in life. Short LTL is associated with increased risk of stiffness and atherosclerosis of the carotid artery, atherosclerotic heart disease, and diminished survival in the elderly.

Keywords

Genetics Telomere pulse wave velocity Arteries Elasticity, arterial aging 

Abbreviations

GWA

Genome-wide association

HPC

Hematopoietic progenitor cell

HSC

Hematopoietic stem cells

LTL

Leukocyte telomere length

PP

Pulse pressure

PWV

Pulse wave velocity

SNPs

Single-nucleotide polymorphisms

References

  1. 1.
    Benetos A, Safar M, Rudnichi A, Smulyan H, Richard J-L, Ducimetiere P, Guize L. Pulse pressure: a predictor of long term cardiovascular mortality in a French male population. Hypertension. 1997;30:1410–5.PubMedCrossRefGoogle Scholar
  2. 2.
    Laurent S, Boutouyrie P, Lacolley P. Structural and genetic bases of arterial stiffness. Hypertension. 2005;45(6):1050–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25(5):932–43.PubMedCrossRefGoogle Scholar
  4. 4.
    Aviv A. Genetics of leukocyte telomere length and its role in atherosclerosis. Mutat Res. 2012;730(1–2):68–74.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci U S A. 1995;92:11190–4.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Aviv A, Levy D, Mangel M. Growth, telomere dynamics and successful and unsuccessful human aging. Mech Ageing Dev. 2003;124:829–37.PubMedCrossRefGoogle Scholar
  7. 7.
    Cawthon RM, Smith KR, O’Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003;361:393–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Benetos A, Okuda K, Lajemi M, et al. Telomere length as an indicator of biological aging: the gender effect and relation with pulse pressure and pulse wave velocity. Hypertension. 2001;37:381–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Brouilette S, Singh RK, Thompson JR, Goodall AH, Samani NJ. White cell telomere length and risk of premature myocardial infarction. Arterioscler Thromb Vasc Biol. 2003;23:842–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Benetos A, Gardner JP, Zureik M, et al. Short telomeres are associated with increased carotid atherosclerosis in hypertensive subjects. Hypertension. 2004;43:182–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Tentolouris N, Nzietchueng R, Cattan V, et al. White blood cells telomere length is shorter in males with type 2 diabetes and microalbuminuria. Diabetes Care. 2007;30:2909–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Youngren K, Jeanclos E, Aviv H, Kimura M, Stock J, Hanna M, et al. Synchrony in telomere length of the human fetus. Hum Genet. 1998;102(6):640–3.PubMedCrossRefGoogle Scholar
  13. 13.
    Codd V, Nelson CP, Albrecht E, Mangino M, Deelen J, Buxton JL, et al. Identification of seven loci affecting mean telomere length and their association with disease. Nat Genet. 2013;45(4):422–7.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Blackburn EH. Telomeres and telomerase: their mechanisms of action and the effects of altering their functions. FEBS Lett. 2005;579(4):859–62.PubMedCrossRefGoogle Scholar
  15. 15.
    Benetos A, Kimura M, Labat C, Buchoff GM, Huber S, Labat L, et al. A model of canine leukocyte telomere dynamics. Aging Cell. 2011;10(6):991–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Aubert G, Baerlocher GM, Vulto I, Poon SS, Lansdorp PM. Collapse of telomere homeostasis in hematopoietic cells caused by heterozygous mutations in telomerase genes. PLoS Genet. 2012;8(5):e1002696.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441(7097):1068–74.PubMedCrossRefGoogle Scholar
  18. 18.
    Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas LF, et al. Obesity, cigarette smoking, and telomere length in women. Lancet. 2005;366(9486):662–4.PubMedCrossRefGoogle Scholar
  19. 19.
    von Zglinicki T. Role of oxidative stress in telomere length regulation and replicative senescence. Ann N Y Acad Sci. 2000;908:99–110.CrossRefGoogle Scholar
  20. 20.
    Benetos A, Kark J, Susser E, Kimura M, Sinnreich R, Chen W, et al. Tracking and fixed ranking of leukocyte telomere length across the adult life course. Aging Cell. 2013;12:615–21.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Daniali L, Benetos A, Susser E, Kark JD, Labat C, Kimura M, et al. Telomeres shorten at equivalent rates in somatic tissues of adults. Nat Commun. 2013;4:1597.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009;361:2353–65.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Benetos A, Gautier S, Ricard S, Topouchian J, Asmar R, Poirier O, et al. Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. Circulation. 1996;94(4):698–703.PubMedCrossRefGoogle Scholar
  24. 24.
    Atwood LD, Samollow PB, Hixson JE, Stern MP, MacCluer JW. Genome-wide linkage analysis of pulse pressure in Mexican Americans. Hypertension. 2001;37(2 Part 2):425–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Camp NJ, Hopkins PN, Hasstedt SJ, Coon H, Malhotra A, Cawthon RM, et al. Genome-wide multipoint parametric linkage analysis of pulse pressure in large, extended Utah pedigrees. Hypertension. 2003;42(3):322–8.PubMedCrossRefGoogle Scholar
  26. 26.
    DeStefano AL, Larson MG, Mitchell GF, Benjamin EJ, Vasan RS, Li J, et al. Genome-wide scan for pulse pressure in the National Heart, Lung and Blood Institute’s Framingham Heart Study. Hypertension. 2004;44(2):152–5.PubMedCrossRefGoogle Scholar
  27. 27.
    Bielinski SJ, Lynch AI, Miller MB, Weder A, Cooper R, Oberman A, et al. Genome-wide linkage analysis for loci affecting pulse pressure: the Family Blood Pressure Program. Hypertension. 2005;46(6):1286–93.PubMedCrossRefGoogle Scholar
  28. 28.
    Franceschini N, MacCluer JW, Rose KM, Rutherford S, Cole SA, Laston S, et al. Genome-wide linkage analysis of pulse pressure in American Indians: the Strong Heart Study. Am J Hypertens. 2008;21(2):194–9.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Turner ST, Peyser PA, Kardia SL, Bielak LF, Sheedy 3rd PF, Boerwinkle E, et al. Genomic loci with pleiotropic effects on coronary artery calcification. Atherosclerosis. 2006;185(2):340–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Levy D, Larson MG, Benjamin EJ, Newton-Cheh C, Wang TJ, Hwang SJ, et al. Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness. BMC Med Genet. 2007;8 Suppl 1:S3.PubMedCrossRefGoogle Scholar
  31. 31.
    Durier S, Fassot C, Laurent S, Boutouyrie P, Couetil JP, Fine E, et al. Physiological genomics of human arteries: quantitative relationship between gene expression and arterial stiffness. Circulation. 2003;108(15):1845–51.PubMedCrossRefGoogle Scholar
  32. 32.
    Fassot C, Briet M, Rostagno P, Barbry P, Perret C, Laude D, et al. Accelerated arterial stiffening and gene expression profile of the aorta in patients with coronary artery disease. J Hypertens. 2008;26(4):747–57.PubMedCrossRefGoogle Scholar
  33. 33.
    Tarasov KV, Sanna S, Scuteri A, Strait JB, Orru M, Parsa A, et al. COL4A1 is associated with arterial stiffness by genome-wide association scan. Circ Cardiovasc Genet. 2009;2(2):151–8.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Wain LV, Verwoert GC, O’Reilly PF, Shi G, Johnson T, Johnson AD, et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat Genet. 2011;43(10):1005–11.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Ganesh SK, Tragante V, Guo W, Guo Y, Lanktree MB, Smith EN, et al. Loci influencing blood pressure identified using a cardiovascular gene-centric array. Hum Mol Genet. 2013;22(8):1663–78.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Hong KW, Oh B. Recapitulation of genome-wide association studies on body mass index in the Korean population. Int J Obes (Lond). 2012;36(8):1127–30.CrossRefGoogle Scholar
  37. 37.
    Kelly TN, Takeuchi F, Tabara Y, Edwards TL, Kim YJ, Chen P, et al. Genome-wide association study meta-analysis reveals transethnic replication of mean arterial and pulse pressure Loci. Hypertension. 2013;62(5):853–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Zintzaras E, Kitsios G, Kent D, Camp NJ, Atwood L, Hopkins PN, et al. Genome-wide scans meta-analysis for pulse pressure. Hypertension. 2007;50(3):557–64.PubMedCrossRefGoogle Scholar
  39. 39.
    Mitchell GF, Verwoert GC, Tarasov KV, Isaacs A, Smith AV, et al. Common genetic variation in the 3′-BCL11B gene desert is associated with carotid-femoral pulse wave velocity and excess cardiovascular disease risk: the AortaGen Consortium. Circ Cardiovasc Genet. 2012;5(1):81–90.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Mitchell GF, DeStefano AL, Larson MG, Benjamin EJ, Chen MH, Vasan RS, et al. Heritability and a genome-wide linkage scan for arterial stiffness, wave reflection, and mean arterial pressure: the Framingham Heart Study. Circulation. 2005;112(2):194–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Turner ST, Fornage M, Jack CR Jr., Mosley TH, Kardia SL, Boerwinkle E, et al. Genomic susceptibility loci for brain atrophy in hypertensive sibships from the GENOA study. Hypertension. 2005;45(4):793–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Aberg K, Dai F, Viali S, Tuitele J, Sun G, Indugula SR, et al. Suggestive linkage detected for blood pressure related traits on 2q and 22q in the population on the Samoan islands. BMC Med Genet. 2009;10:107.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Kochunov P, Glahn D, Lancaster J, Winkler A, Kent JW, Jr., Olvera RL, et al. Whole brain and regional hyperintense white matter volume and blood pressure: overlap of genetic loci produced by bivariate, whole-genome linkage analyses. Stroke. 2010;41(10):2137–42.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Simino J, Shi G, Arnett D, Broeckel U, Hunt SC, Rao DC. Variants on chromosome 6p22.3 associated with blood pressure in the HyperGEN study: follow-up of FBPP quantitative trait loci. Am J Hypertens. 2011;24(11):1227–33.Google Scholar
  45. 45.
    Zhang D, Pang Z, Li S, Jiang W, Wang S, Thomassen M, et al. Genome-wide linkage and association scans for pulse pressure in Chinese twins. Hypertens Res. 2012;35(11):1051–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag London 2014

Authors and Affiliations

  • Athanase Benetos
    • 1
    • 2
    Email author
  • Abraham Aviv
    • 3
  • Patrick Lacolley
    • 4
  • Michel E. Safar
    • 5
  • Véronique Regnault
    • 4
  1. 1.Department of GeriatricsUniversity Hospital of Nancy, Université De LorraineVandoeuvre Les NancyFrance
  2. 2.INSERM, U1116, Université de LorraineNancyFrance
  3. 3.Center of Human Development and Aging RutgersThe State University of New Jersey, New Jersey Medical SchoolNewarkUSA
  4. 4.Unité INSERM U1116Université de Lorraine, Faculté de MédecineVandoeuvre Les NancyFrance
  5. 5.Department of MedicineParis Descartes University, Assistance Publique des Hôpitaux de Paris, Hôtel-Dieu Hospital, Diagnosis and Therapeutic CenterParisFrance

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