Abstract
Objective
The influence of T-786C polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) on arteriosclerotic parameters by age and gender were examined.
Methods
Brachial-ankle pulse wave velocity (baPWV), heart-rate adjusted augmentation index (AIx@75), pulse pressure (PP) and albumin–creatinine ratio (ACR) were assessed as arteriosclerotic parameters in addition to non-high-density lipoprotein cholesterol (non-HDL-C) to HDL-C (non-HDL-C/HDL-C) ratio in 1499 participants. T-786C polymorphism (rs2070744) was screened using a TaqMan allelic discrimination assay. Analyses of covariance were carried.
Results
Women with the non-C allele showed significantly lower AIx@75 in participants aged <65 years and baPWV in participants aged ≥65 years than those with C allele. In contrast, men with the non-C allele showed significantly higher PP in participants aged <65 years, and higher ACR and non-HDL-C/HDL-C ratio in participants aged ≥65 years. In men on cholesterol-lowering medication, the non-C allele carriers showed significantly higher non-HDL-C compared to those in the C allele carriers.
Conclusions
eNOS T-786C polymorphism is significantly associated with arteriosclerotic parameters accompanied with age and gender differences, possibly involving antioxidative and/or endothelial signaling other than inflammatory signaling.
Similar content being viewed by others
References
Cecelja M, Chowienczyk P. Role of arterial stiffness in cardiovascular disease. JRSM Cardiovasc Dis. 2012;1(4):11.
Shirwany NA, Zou MH. Arterial stiffness: a brief review. Acta Pharmacol Sin. 2010;31:1267–76.
Vanhoutte PM, Shimokawa H, Tang EH, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol (Oxf). 2009;196:193–222.
Cortese-Krott MM, Kelm M. Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function? Redox Biol. 2014;2:251–8.
Lowenstein CJ, Michel T. What’s in a name? eNOS and anaphylactic shock. J Clin Invest. 2006;116:2075–8.
Peng X, Haldar S, Deshpande S, Irani K, Kass DA. Wall stiffness suppresses Akt/eNOS and cytoprotection in pulse-perfused endothelium. Hypertension. 2003;41:378–81.
Rossi GP, Maiolino G, Zanchetta M, Sticchi D, Pedon L, Cesari M, et al. The T(-786)C endothelial nitric oxide synthase genotype predicts cardiovascular mortality in high-risk patients. J Am Coll Cardiol. 2006;48:1166–74.
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, et al. T-786→C mutation in the 5′-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation. 1999;99:2864–70.
Li J, Wu X, Li X, Feng G, He L, Shi Y. The endothelial nitric oxide synthase gene is associated with coronary artery disease: a meta-analysis. Cardiology. 2010;116:271–8.
Niu W, Qi Y. An updated meta-analysis of endothelial nitric oxide synthase gene: three well-characterized polymorphisms with hypertension. PLoS One. 2011;6:e24266.
Wang M, Jiang X, Wu W, Zhang D. Endothelial NO synthase gene polymorphisms and risk of ischemic stroke in Asian population: a meta-analysis. PLoS One. 2013;8:e60472.
Zeng Z, Li L, Zhang Z, Li Y, Wei Z, Huang K, et al. A meta-analysis of three polymorphisms in the endothelial nitric oxide synthase gene (NOS3) and their effect on the risk of diabetic nephropathy. Hum Genet. 2010;127:373–81.
Kals J, Kampus P, Kals M, Pulges A, Teesalu R, Zilmer M. Effects of stimulation of nitric oxide synthesis on large artery stiffness in patients with peripheral arterial disease. Atherosclerosis. 2006;185:368–74.
Cakar M, Bulucu F, Karaman M, Ay SA, Kurt O, Balta S, et al. Asymmetric dimethylarginine and augmentation index in newly diagnosed patients with hypertension. Angiology. 2015;66:43–8.
Weber T, Maas R, Auer J, Lamm G, Lassnig E, Rammer M, et al. Arterial wave reflections and determinants of endothelial function a hypothesis based on peripheral mode of action. Am J Hypertens. 2007;20:256–62.
Masaki N, Hakuno D, Toya T, Shiraishi Y, Kujiraoka T, Namba T, et al. Association between brachial-ankle pulse wave velocity and the ratio of l-arginine to asymmetric dimethylarginine in patients undergoing coronary angiography. J Cardiol. 2015;65:311–7
Rosenbaum D, Giral P, Chapman J, Rached FH, Kahn JF, Bruckert E, et al. Radial augmentation index is a surrogate marker of atherosclerotic burden in a primary prevention cohort. Atherosclerosis. 2013;231:436–41.
Mineo C, Yuhanna IS, Quon MJ, Shaul PW. High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases. J Biol Chem. 2003;278:9142–9.
Zhao W, Gong W, Wu N, Li Y, Ye K, Lu B, et al. Association of lipid profiles and the ratios with arterial stiffness in middle-aged and elderly Chinese. Lipids Health Dis. 2014;13:37.
Eliasson B, Cederholm J, Eeg-Olofsson K, Svensson AM, Zethelius B, Gudbjornsdottir S, et al. Clinical usefulness of different lipid measures for prediction of coronary heart disease in type 2 diabetes: a report from the Swedish National Diabetes Register. Diabetes Care. 2011;34:2095–100.
Liu CS, Pi-Sunyer FX, Li CI, Davidson LE, Li TC, Chen W, et al. Albuminuria is strongly associated with arterial stiffness, especially in diabetic or hypertensive subjects–a population-based study (Taichung Community Health Study, TCHS). Atherosclerosis. 2010;211:315–21.
Miyai N, Utsumi M, Gowa Y, Igarashi Y, Miyashita K, Takeda S, et al. Age-specific nomogram of brachial-ankle pulse wave velocity in Japanese adolescents. Clin Exp Hypertens. 2013;35:95–101.
Yamashina A, Tomiyama H, Takeda K, Tsuda H, Arai T, Hirose K, et al. Validity, reproducibility, and clinical significance of noninvasive brachial-ankle pulse wave velocity measurement. Hypertens Res. 2002;25:359–64.
Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ. The influence of heart rate on augmentation index and central arterial pressure in humans. J Physiol. 2000;525(Pt 1):263–70.
Lekakis JP, Ikonomidis I, Tsibida M, Protogerou A, Papada A, Papapanagiotou A, et al. Genetic variations of the endothelial nitric oxide synthase gene are related to increased levels of C-reactive protein and macrophage-colony stimulating-factor in patients with coronary artery disease. Thromb Haemost. 2006;96:520–8.
Liu Y, Burdon KP, Langefeld CD, Beck SR, Wagenknecht LE, Rich SS, et al. T-786C polymorphism of the endothelial nitric oxide synthase gene is associated with albuminuria in the diabetes heart study. J Am Soc Nephrol. 2005;16:1085–90.
Duckles SP, Miller VM. Hormonal modulation of endothelial NO production. Pflug Arch. 2010;459:841–51.
Gavin KM, Seals DR, Silver AE, Moreau KL. Vascular endothelial estrogen receptor alpha is modulated by estrogen status and related to endothelial function and endothelial nitric oxide synthase in healthy women. J Clin Endocrinol Metab. 2009;94:3513–20.
Goglia L, Tosi V, Sanchez AM, Flamini MI, Fu XD, Zullino S, et al. Endothelial regulation of eNOS, PAI-1 and t-PA by testosterone and dihydrotestosterone in vitro and in vivo. Mol Hum Reprod. 2010;16:761–9.
Venturelli E, Galimberti D, Lovati C, Fenoglio C, Scalabrini D, Mariani C, et al. The T-786C NOS3 polymorphism in Alzheimer’s disease: association and influence on gene expression. Neurosci Lett. 2005;382:300–3.
McEniery CM, Yasmin Hall IR, Qasem A, Wilkinson IB, Cockcroft JR, et al. Normal vascular aging: differential effects on wave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol. 2005;46:1753–60.
Baylis C, Vallance P. Measurement of nitrite and nitrate levels in plasma and urine—what does this measure tell us about the activity of the endogenous nitric oxide system? Curr Opin Nephrol Hypertens. 1998;7:59–62.
Nagassaki S, Metzger IF, Souza-Costa DC, Marroni AS, Uzuelli JA, Tanus-Santos JE. eNOS genotype is without effect on circulating nitrite/nitrate level in healthy male population. Thromb Res. 2005;115:375–9.
Salimi S, Naghavi A, Firoozrai M, Zand H, Tavilani H, Nakhaee A, et al. Association of plasma nitric oxide concentration and endothelial nitric oxide synthase T-786C gene polymorphism in coronary artery disease. Pathophysiology. 2012;19:157–62.
Förstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace. Circulation. 2006;113:1708–14.
Nagassaki S, Sertorio JT, Metzger IF, Bem AF, Rocha JB, Tanus-Santos JE. eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite. Free Radic Biol Med. 2006;41:1044–9.
Souza-Costa DC, Sandrim VC, Lopes LF, Gerlach RF, Rego EM, Tanus-Santos JE. Anti-inflammatory effects of atorvastatin: modulation by the T-786C polymorphism in the endothelial nitric oxide synthase gene. Atherosclerosis. 2007;193:438–44.
Zago VH, Santos JE, Danelon MR, Silva RM, Panzoldo NB, Parra ES, et al. Effects of atorvastatin and T-786C polymorphism of eNOS gene on plasma metabolic lipid parameters. Arq Bras Cardiol. 2013;100:14–20.
Metzger IF, Souza-Costa DC, Marroni AS, Nagassaki S, Desta Z, Flockhart DA, et al. Endothelial nitric oxide synthase gene haplotypes associated with circulating concentrations of nitric oxide products in healthy men. Pharmacogenet Genom. 2005;15:565–70.
da Silva RF, Sertorio JT, Lacchini R, Trape AA, Tanus-Santos JE, Rush JW, et al. Influence of training status and eNOS haplotypes on plasma nitrite concentrations in normotensive older adults: a hypothesis-generating study. Aging Clin Exp Res. 2014;26:591–8.
Liu D, Jiang Z, Dai L, Zhang X, Yan C, Han Y. Association between the—786T> C 1polymorphism in the promoter region of endothelial nitric oxide synthase (eNOS) and risk of coronary artery disease: a systematic review and meta-analysis. Gene. 2014;545:175–83.
Acknowledgments
This work was supported by the Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (25460811 and 25350894). We are grateful to Dr. Mitsuru Shiba, Dr. Yuji Uematsu and Ms. Momoko Buyo of Wakayama Medical University for their supports in the examination of participants. We are also grateful to Ms. Mami Murao and Mr. Yushiro Kagami for their participation in the genotyping. We also wish to thank Ms. Toshiko Hanamitsu, a public health nurse, and other members of the Public office on-site in for their assistances in locating and scheduling participants for examinations. We also thank Ms. Yuko Kuwabara for her assistance with data reduction and administration.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
No conflicts of interest, financial or otherwise, are declared by the authors.
Rights and permissions
About this article
Cite this article
Hashimoto, M., Miyai, N., Hattori, S. et al. Age and gender differences in the influences of eNOS T-786C polymorphism on arteriosclerotic parameters in general population in Japan. Environ Health Prev Med 21, 274–282 (2016). https://doi.org/10.1007/s12199-016-0527-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12199-016-0527-1