Effects of endothelin-related gene polymorphisms and aerobic exercise habit on age-related arterial stiffening: a 10-yr longitudinal study.

Increased arterial stiffness has emerged as a strong predictor of future cardiovascular events and all-cause mortality. The aim of this study was to elucidate influences of endothelin (ET)-related genetic polymorphisms and regular physical activity on age-related arterial stiffening through a 10-yr longitudinal study. A decadal change in brachial-ankle pulse wave velocity (baPWV), an index of arterial stiffness, was evaluated retrospectively among 92 volunteers (63 ± 14 yr, 51 men). The targeted single-nucleotide polymorphisms were ET-A receptor SNP rs5333 (ET-A) and ET-B receptor SNP rs5351 (ET-B). Subjects with either ET-A TC or CC genotypes exhibited significantly greater increases in baPWV (+15.3 ± 11.7 and +16.6 ± 15.7%/dec, respectively) than ET-A TT genotype holders (+9.2 ± 9.0%/dec), whereas subjects with the ET-B GG genotype showed a significantly greater increase in baPWV (+17.7 ± 14.1%/dec) than other ET-B genotype holders (AA: +9.5 ± 10.0%/dec; AG: +11.2 ± 9.6%/dec). The combination of these ET-related genetic risks was associated with a 2.4 times greater decadal increase in baPWV compared with no genetic risk (+8.1 ± 8.4 vs. 19.5 ± 16.0%/dec). In contrast, individuals engaging in >15 METs·h/wk of aerobic exercise showed substantially smaller increases in baPWV (+5.0 ± 9.7%/dec) compared with their physically inactive peers (approximately +13%/dec). These differences remained significant after adjusting for confounding factors, including baseline baPWV and ET-related genotype risk. Our current longitudinal study found that ET-related gene polymorphisms contribute to diverse age-related changes in arterial stiffness, and that regular sufficient aerobic exercise attenuates the age-related arterial stiffening independently of ET-related gene polymorphisms. NEW & NOTEWORTHY This 10-yr longitudinal study suggests that endothelin-related gene polymorphisms contribute to divergent increases in arterial stiffness with advancing age, whereas regular sufficient aerobic exercise attenuates age-related arterial stiffening independently of ET-related gene polymorphisms. This notion partly supports prevailing evidence that regular aerobic exercise contributes to a lower incidence of cardiovascular disease.

[1]  K. Kario,et al.  Brachial-Ankle Pulse Wave Velocity and the Risk Prediction of Cardiovascular Disease: An Individual Participant Data Meta-Analysis , 2017, Hypertension.

[2]  G. Pierce,et al.  Habitual aerobic exercise does not protect against micro- or macrovascular endothelial dysfunction in healthy estrogen-deficient postmenopausal women. , 2017, Journal of applied physiology.

[3]  M. J. Nowlan,et al.  Reduced large elastic artery stiffness with regular aerobic exercise in middle-aged and older adults: potential role of suppressed nuclear factor &kgr; B signalling , 2015, Journal of hypertension.

[4]  S. Maeda,et al.  Aerobic exercise training decreases plasma asymmetric dimethylarginine concentrations with increase in arterial compliance in postmenopausal women. , 2014, American journal of hypertension.

[5]  Hirofumi Tanaka,et al.  Central artery stiffness, neuropsychological function, and cerebral perfusion in sedentary and endurance-trained middle-aged adults , 2013, Journal of hypertension.

[6]  K. Moreau,et al.  Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women. , 2013, The Journal of clinical endocrinology and metabolism.

[7]  C. Vlachopoulos,et al.  Prediction of Cardiovascular Events and All-Cause Mortality With Brachial-Ankle Elasticity Index: A Systematic Review and Meta-Analysis , 2012, Hypertension.

[8]  Roy J. Shephard,et al.  2011 Compendium of Physical Activities: A Second Update of Codes and MET Values , 2012 .

[9]  David R Bassett,et al.  2011 Compendium of Physical Activities: a second update of codes and MET values. , 2011, Medicine and science in sports and exercise.

[10]  G. Pierce,et al.  Sex-specific effects of habitual aerobic exercise on brachial artery flow-mediated dilation in middle-aged and older adults. , 2011, Clinical science.

[11]  H. Murakami,et al.  Lack of carotid stiffening associated with MTHFR 677TT genotype in cardiorespiratory fit adults. , 2010, Physiological genomics.

[12]  Tetsuo Shoji,et al.  Brachial-ankle pulse wave velocity as an index of central arterial stiffness. , 2010, Journal of atherosclerosis and thrombosis.

[13]  C. Vlachopoulos,et al.  Prediction of Cardiovascular Events and All-Cause Mortality With Arterial Stiffness , 2011 .

[14]  C. DeSouza,et al.  Sex differences in endothelin-1-mediated vasoconstrictor tone in middle-aged and older adults. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[15]  Tetsuo Shoji,et al.  Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness , 2009, Journal of hypertension.

[16]  J. Sugawara,et al.  Reduction in alpha-adrenergic receptor-mediated vascular tone contributes to improved arterial compliance with endurance training. , 2009, International journal of cardiology.

[17]  J. Sugawara,et al.  Involvement of endothelin‐1 in habitual exercise‐induced increase in arterial compliance , 2009, Acta physiologica.

[18]  John J. Evans,et al.  Regulation of endothelin-1 release from human endothelial cells by sex steroids and angiotensin-II , 2008, Peptides.

[19]  J. Sugawara,et al.  Arterial Stiffness, Physical Activity, and Atrial Natriuretic Peptide Gene Polymorphism in Older Subjects , 2008, Hypertension Research.

[20]  J. Sugawara,et al.  Estrogen receptor-alpha genotype affects exercise-related reduction of arterial stiffness. , 2008, Medicine and science in sports and exercise.

[21]  C. DeSouza,et al.  Endothelin-1 Vasoconstrictor Tone Increases With Age in Healthy Men But Can Be Reduced by Regular Aerobic Exercise , 2007, Hypertension.

[22]  A. Bauman,et al.  Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association. , 2007, Circulation.

[23]  D. Levy,et al.  Vascular Stiffness and Genetic Variation at the Endothelial Nitric Oxide Synthase Locus: The Framingham Heart Study , 2007, Hypertension.

[24]  J. Sugawara,et al.  Physical activity duration, intensity, and arterial stiffening in postmenopausal women. , 2006, American journal of hypertension.

[25]  J. Sugawara,et al.  Polymorphism in Endothelin-Related Genes Limits Exercise-Induced Decreases in Arterial Stiffness in Older Subjects , 2006, Hypertension.

[26]  G. Bricca,et al.  A1166C polymorphism of angiotensin II type 1 receptor, blood pressure and arterial stiffness in hypertension , 2004, Journal of hypertension.

[27]  Yen-Ling Chen,et al.  17β-Estradiol inhibits cyclic strain-induced endothelin-1 gene expression within vascular endothelial cells , 2004 .

[28]  E. Boerwinkle,et al.  Nitric oxide synthase gene polymorphism (G894T) influences arterial stiffness in adults: The Bogalusa Heart Study. , 2004, American journal of hypertension.

[29]  Yen-Ling Chen,et al.  17beta-estradiol inhibits cyclic strain-induced endothelin-1 gene expression within vascular endothelial cells. , 2004, American journal of physiology. Heart and circulatory physiology.

[30]  Ahmad Qasem,et al.  Endothelin-1 regulates arterial pulse wave velocity in vivo. , 2003, Journal of the American College of Cardiology.

[31]  D. Seals.  Habitual Exercise and the Age-Associated Decline in Large Artery Compliance , 2003, Exercise and sport sciences reviews.

[32]  K. Moreau,et al.  Regular exercise, hormone replacement therapy and the age-related decline in carotid arterial compliance in healthy women. , 2003, Cardiovascular research.

[33]  Shigeaki Hinohara,et al.  Influences of age and gender on results of noninvasive brachial-ankle pulse wave velocity measurement--a survey of 12517 subjects. , 2003, Atherosclerosis.

[34]  A. Yamashina,et al.  Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. , 2002, Hypertension research : official journal of the Japanese Society of Hypertension.

[35]  F. Cambien,et al.  Endothelin gene variants and aortic and cardiac structure in never-treated hypertensives. , 2001, American journal of hypertension.

[36]  L. Ghiadoni,et al.  Age-Related Reduction of NO Availability and Oxidative Stress in Humans , 2001, Hypertension.

[37]  M. Safar,et al.  Therapeutic studies and arterial stiffness in hypertension: recommendations of the European Society of Hypertension , 2000, Journal of hypertension.

[38]  Hirofumi Tanaka,et al.  Regular Aerobic Exercise Prevents and Restores Age-Related Declines in Endothelium-Dependent Vasodilation in Healthy Men , 2000, Circulation.

[39]  Hirofumi Tanaka,et al.  Aging, Habitual Exercise, and Dynamic Arterial Compliance , 2000, Circulation.

[40]  A. Ehsani,et al.  Enhanced endothelium-dependent vasodilation in older endurance-trained men. , 2000, Journal of applied physiology.

[41]  T. Masaki,et al.  Pathophysiology of endothelin in the cardiovascular system. , 1999, Annual review of physiology.

[42]  R. Carretta.  McDonaldʼs Blood Flow in Arteries: Theoretical, Experimental and Clinical Principles , 1998 .

[43]  Hirofumi Tanaka,et al.  Absence of age-related increase in central arterial stiffness in physically active women. , 1998, Arteriosclerosis, thrombosis, and vascular biology.

[44]  F. Cambien,et al.  Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients. , 1996, Circulation.

[45]  J. Fleg,et al.  Effects of Age and Aerobic Capacit on Arterial Stiffness in Healthy Adults , 1993, Circulation.

[46]  A. Lerman,et al.  Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. , 1991, The New England journal of medicine.

[47]  M. Yanagisawa,et al.  Involvement of endothelin in the regulation of human vascular tonus. Potent vasoconstrictor effect and existence in endothelial cells. , 1990, Circulation.

[48]  R. Shephard,et al.  A simple method to assess exercise behavior in the community. , 1969, Canadian journal of applied sport sciences. Journal canadien des sciences appliquees au sport.

[49]  A P Avolio,et al.  Effects of aging on changing arterial compliance and left ventricular load in a northern Chinese urban community. , 1983, Circulation.