Roles of eNOS in atherosclerosis treatment

  • Fen-fang Hong
  • Xiao-yu Liang
  • Wei Liu
  • Sha Lv
  • Shu-jin He
  • Hai-bin KuangEmail author
  • Shu-long YangEmail author



Atherosclerosis (AS) is the main pathogeny of coronary heart disease, cerebral infarction and peripheral vascular disease. Endothelial dysfunction is one of the important pathogenesis of AS. As an important endothelium-derived relaxation factor, nitric oxide (NO) plays a role in cardiovascular protection and anti-AS function; but in the pathological state, endothelial nitric oxide synthase (eNOS) disorder causes an abnormal production of NO, which may damage endothelial function and trigger AS. This review summarized the research progresses in the treatment strategies for AS based on correcting the disordered eNOS/ NO signaling pathway.

Main body

According to the topic, select the search terms ‘atherosclerosis,’ ‘nitric oxide,’ ‘eNOS,’ ‘treatment,’ ‘management,’ ‘medication,’ ‘maintenance,’ ‘remission’. Using these terms, a structured literature search via multiple electronic databases was performed for the most recent trial evidence in recent years. We read and analyze these literatures carefully, classified these literatures according to their content, and then summarized and outlined the common main points in these classified literatures. Finally, literature data were organized to discuss these main points logically. We found that both aberrant expression and dysfunction of eNOS are closely related to AS development, and some new treatment strategies aimed at eNOS have been proposed, including upregulation of eNOS expression and inhibition of eNOS uncoupling. The former one is mainly related to inflammatory inhibition and protection of the PKB-eNOS signaling pathway; whereas the latter one is associated with the addition of the L-arginine substrate of eNOS, arginase inhibition, and the supplement of tetrahydrobiopterin, which can elevate no level.


eNOS can be an important target for prevention and treatment of AS, and eNOS drugs may be another potent class of effective therapeutic treatment for AS following traditional lipid-lowering, anti-platelet, vasodilator drugs. But applying these experimental results to clinic treatment still requires further studies and development of biotechnology.


Atherosclerosis Endothelial nitric oxide synthase Arginase Tetrahydrobiopterin Treatment 



This work was supported by National Natural Science Foundation of China (nos. 81660751, 81660151 and 81260504); Key Research and Development Program of Jiangxi Province of China (no. 20161BBG70067) and Jiangxi Provincial Natural Science Foundation of China (no. 20171BAB205085).

Author contributions

XL and HK contributed to paper revision and writing promotion in grammars and languages; WeiL, SL and SH wrote the paper; FH and SY are responsible for the idea and fund.


  1. 1.
    Ke YN, Liu Y. Cholesterol depressing and atherosclerosis prevention. Health Care Elder. 2016;1:8–9.Google Scholar
  2. 2.
    Younk LM, Lamos EM, Davis SN. The cardiovascular effects of insulin. Expert Opin Drug Saf. 2014;13:955–66.CrossRefGoogle Scholar
  3. 3.
    Lurie A. Endothelial dysfunction in adults with obstructive sleep apnea. Adv Cardiol. 2011;46:139–70.CrossRefGoogle Scholar
  4. 4.
    Zhang HP, Tang N, Ka B. Endothelial nitric oxide synthase uncoupling and oxidative stress. Traditional Chinese Medicine J Liaoning Univ. 2009;11:36–40.Google Scholar
  5. 5.
    Sukhovershin RA, Yepuri G, Ghebremariam YT. endothelium-derived nitric oxide as an antiatherogenic mechanism: implications for therapy. Methodist Debakey Cardiovasc J. 1900;11:166–71.CrossRefGoogle Scholar
  6. 6.
    Saini V, Bhatnagar MK, Bhattacharjee J. Endothelial nitric oxide synthase Glu298Asp (G894T) gene polymorphism in coronary artery disease patients with type 2 diabetes mellitus. Diabetes Metab Syndr. 2012;6:106–9.CrossRefGoogle Scholar
  7. 7.
    Xin G, Li S, Fu YM, Yong Z. Effects of olmesartan on endothelial progenitor cell mobilization and function in carotid atherosclerosis. Med Sci Monit Int Med J Exp Clin Res. 2015;21:1189–93.Google Scholar
  8. 8.
    Scalia R, Stalker TJ. Microcirculation as a target for the anti-inflammatory properties of statins. Microcirculation. 2002;9:431–42.CrossRefGoogle Scholar
  9. 9.
    Xu L, Wang S, Li B, Sun A, Zou Y, Ge J. A protective role of ciglitazone in ox-LDL-induced rat microvascular endothelial cells via modulating PPARgamma-dependent AMPK/eNOS pathway. J Cell Mol Med. 2015;19:92–102.CrossRefGoogle Scholar
  10. 10.
    Yin J, Huang F, Yi Y, Yin L, Peng D. EGCG attenuates atherosclerosis through the Jagged-1/Notch pathway. Int J Mol Med. 2016;37:398–406.CrossRefGoogle Scholar
  11. 11.
    Bao MH, Zhang YW, Lou XY, Xiao Y, Cheng Y, Zhou HH. Puerarin protects endothelial cells from oxidized low density lipoprotein induced injuries via the suppression of LOX-1 and induction of eNOS. Can J Physiol Pharmacol. 2014;92:299–306.CrossRefGoogle Scholar
  12. 12.
    Yu S, Wong SL, Lau CW, Huang Y, Yu CM. Oxidized LDL at low concentration promotes in-vitro angiogenesis and activates nitric oxide synthase through PI3K/Akt/eNOS pathway in human coronary artery endothelial cells. Biochem Biophys Res Commun. 2011;407:44–8.CrossRefGoogle Scholar
  13. 13.
    Tsai KL, Huang YH, Kao CL, Yang DM, Lee HC, Chou HY, et al. A novel mechanism of coenzyme Q10 protects against human endothelial cells from oxidative stress-induced injury by modulating NO-related pathways. J Nutr Biochem. 2012;23:458–68.CrossRefGoogle Scholar
  14. 14.
    Imachi H, Murao K. HDL metabolism in lifestyle-related illnesses. Rinsho Byori. 2012;60:1081–6.Google Scholar
  15. 15.
    Durante A, Peretto G, Laricchia A, Ancona F, Spartera M, Mangieri A, et al. Role of the renin–angiotensin–aldosterone system in the pathogenesis of atherosclerosis. Curr Pharm Des. 2012;18:981–1004.CrossRefGoogle Scholar
  16. 16.
    Qaradakhi T, Apostolopoulos V, Zulli A. Angiotensin (1–7) and Alamandine: Similarities and differences. Pharmacol Res. 2016;111:820–6.CrossRefGoogle Scholar
  17. 17.
    Aoyama T, Minatoguchi S. The effect of ARB on prevention of atherosclerosis. Nihon Rinsho. 2011;69:92–9.Google Scholar
  18. 18.
    Fu R, Chen Z, Wang Q, Guo Q, Xu J, Wu X. XJP-1, a novel ACEI, with anti-inflammatory properties in HUVECs. Atherosclerosis. 2011;219:40–8.CrossRefGoogle Scholar
  19. 19.
    Stegbauer J, Potthoff SA, Quack I, Mergia E, Clasen T, Friedrich S, et al. Chronic treatment with angiotensin-(1–7) improves renal endothelial dysfunction in apolipoproteinE-deficient mice. Br J Pharmacol. 2011;163:974–83.CrossRefGoogle Scholar
  20. 20.
    Kljajic ST, Widdop RE, Vinh A, Welungoda I, Bosnyak S, Jones ES, et al. Direct AT(2) receptor stimulation is athero-protective and stabilizes plaque in apolipoprotein E-deficient mice. Int J Cardiol. 2013;169:281–7.CrossRefGoogle Scholar
  21. 21.
    Kilic U, Gok O, Elibol-Can B, Uysal O, Bacaksiz A. Efficacy of statins on sirtuin 1 and endothelial nitric oxide synthase expression: the role of sirtuin 1 gene variants in human coronary atherosclerosis. Clin Exp Pharmacol Physiol. 2015;42:321–30.CrossRefGoogle Scholar
  22. 22.
    Balakumar P, Kathuria S, Taneja G, Kalra S, Mahadevan N. Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J Mol Cell Cardiol. 2012;52:83–92.CrossRefGoogle Scholar
  23. 23.
    Berthe MC, Bernard M, Rasmusen C, Darquy S, Cynober L, Couderc R. Arginine or citrulline associated with a statin stimulates nitric oxide production in bovine aortic endothelial cells. Eur J Pharmacol. 2011;670:566–70.CrossRefGoogle Scholar
  24. 24.
    Ota H, Eto M, Ogawa S, Iijima K, Akishita M, Ouchi Y. SIRT1/eNOS axis as a potential target against vascular senescence, dysfunction and atherosclerosis. J Atheroscler Thromb. 2010;17:431–5.CrossRefGoogle Scholar
  25. 25.
    Mattagajasingh I, Kim CS, Naqvi A, Yamamori T, Hoffman TA, Jung SB, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci USA. 2007;104:14855–60.CrossRefGoogle Scholar
  26. 26.
    Ota H, Akishita M, Eto M, Iijima K, Kaneki M, Ouchi Y. Sirt1 modulates premature senescence-like phenotype in human endothelial cells. J Mol Cell Cardiol. 2007;43:571–9.CrossRefGoogle Scholar
  27. 27.
    Liu X, Ma D, Zheng S, Zha K, Feng J, Cai Y, et al. The roles of nitric oxide and hydrogen sulfide in the anti-atherosclerotic effect of atorvastatin. J Cardiovasc Med (Hagerstown). 2015;16:22–8.CrossRefGoogle Scholar
  28. 28.
    Li T, Li D, Xu H, Zhang H, Tang D, Cao H. Wen-Xin Decoction ameliorates vascular endothelium dysfunction via the PI3K/AKT/eNOS pathway in experimental atherosclerosis in rats. BMC Complement Altern Med. 2016;16:27.CrossRefGoogle Scholar
  29. 29.
    Ren Y, Tao S, Zheng S, Zhao M, Zhu Y, Yang J, et al. Salvianolic acid B improves vascular endothelial function in diabetic rats with blood glucose fluctuations via suppression of endothelial cell apoptosis. Eur J Pharmacol. 2016;791:308–15.CrossRefGoogle Scholar
  30. 30.
    Hong SH, Kim M, Noh JS, Song YO. Perilla oil reduces fatty streak formation at aortic sinus via attenuation of plasma lipids and regulation of nitric oxide synthase in ApoE KO mice. Lipids. 2016;51:1161–70.CrossRefGoogle Scholar
  31. 31.
    Horigome S, Yoshida I, Ito S, Inohana S, Fushimi K, Nagai T, et al. Inhibitory effects of Kaempferia parviflora extract on monocyte adhesion and cellular reactive oxygen species production in human umbilical vein endothelial cells. Eur J Nutr. 2017;56:949–64.CrossRefGoogle Scholar
  32. 32.
    Ichimura M, Kato S, Tsuneyama K, Matsutake S, Kamogawa M, Hirao E, et al. Phycocyanin prevents hypertension and low serum adiponectin level in a rat model of metabolic syndrome. Nutr Res. 2013;33:397–405.CrossRefGoogle Scholar
  33. 33.
    Xiang W, He XJ, Ma YL, Yi ZW, Cao Y, Zhao SP, et al. [1,25(OH)(2)D(3) influences endothelial cell proliferation, apoptosis and endothelial nitric oxide synthase expression of aorta in apolipoprotein E-deficient mice]. Zhonghua Er Ke Za Zhi. 2011;49:829–33.Google Scholar
  34. 34.
    Porto ML, Lima LC, Pereira TM, Nogueira BV, Tonini CL, Campagnaro BP, et al. Mononuclear cell therapy attenuates atherosclerosis in apoE KO mice. Lipids Health Dis. 2011;10:155.CrossRefGoogle Scholar
  35. 35.
    Xu S, Ha CH, Wang W, Xu X, Yin M, Jin FQ, et al. PECAM1 regulates flow-mediated Gab1 tyrosine phosphorylation and signaling. Cell Signal. 2016;28:117–24.CrossRefGoogle Scholar
  36. 36.
    Dai Y, Mehta JL, Chen M. Glucagon-like peptide-1 receptor agonist liraglutide inhibits endothelin-1 in endothelial cell by repressing nuclear factor-kappa B activation. Cardiovasc Drugs Ther. 2013;27:371–80.CrossRefGoogle Scholar
  37. 37.
    Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S, Coutinho P, et al. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation. 2013;127:2209–21.CrossRefGoogle Scholar
  38. 38.
    Notsu Y, Yano S, Shibata H, Nagai A, Nabika T. Plasma arginine/ADMA ratio as a sensitive risk marker for atherosclerosis: Shimane CoHRE study. Atherosclerosis. 2015;239:61–6.CrossRefGoogle Scholar
  39. 39.
    Li Q, Youn JY, Cai H. Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension. J Hypertens. 2015;33:1128–36.CrossRefGoogle Scholar
  40. 40.
    Xie L, Talukder MA, Sun J, Varadharaj S, Zweier JL. Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. J Mol Cell Cardiol. 2015;86:14–22.CrossRefGoogle Scholar
  41. 41.
    Vasquez-Vivar J, Kalyanaraman B, Martasek P. The role of tetrahydrobiopterin in superoxide generation from eNOS: enzymology and physiological implications. Free Radic Res. 2003;37:121–7.CrossRefGoogle Scholar
  42. 42.
    Sugiyama T, Levy BD, Michel T. Tetrahydrobiopterin recycling, a key determinant of endothelial nitric-oxide synthase-dependent signaling pathways in cultured vascular endothelial cells. J Biol Chem. 2009;284:12691–700.CrossRefGoogle Scholar
  43. 43.
    Kim HJ, Son J, Jin E, Lee J, Park S. Effects of exercise and l-arginine intake on inflammation in aorta of high-fat diet induced obese rats. J Exerc Nutr Biochem. 2016;20:36–40.Google Scholar
  44. 44.
    Nguyen MC, Park JT, Jeon YG, Jeon BH, Hoe KL, Kim YM, et al. Arginase inhibition restores peroxynitrite-induced endothelial dysfunction via l-arginine-dependent endothelial nitric oxide synthase phosphorylation. Yonsei Med J. 2016;57:1329–38.CrossRefGoogle Scholar
  45. 45.
    Bahadoran Z, Mirmiran P, Tahmasebinejad Z, Azizi F. Dietary l-arginine intake and the incidence of coronary heart disease: Tehran lipid and glucose study. Nutr Metab (Lond). 2016;13:23.CrossRefGoogle Scholar
  46. 46.
    Luiking YC, Deutz NE. Biomarkers of arginine and lysine excess. J Nutr. 2007;137:1662S–1668S.CrossRefGoogle Scholar
  47. 47.
    You H, Gao T, Cooper TK, Morris SM Jr, Awad AS. Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy. Am J Physiol Renal Physiol. 2015;309:F447-55.CrossRefGoogle Scholar
  48. 48.
    Yang Z, Ming XF. Arginase: the emerging therapeutic target for vascular oxidative stress and inflammation. Front Immunol. 2013;4:149.CrossRefGoogle Scholar
  49. 49.
    Ryoo S, Berkowitz DE, Lim HK. Endothelial arginase II and atherosclerosis. Korean J Anesthesiol. 2011;61:3–11.CrossRefGoogle Scholar
  50. 50.
    Pham TN, Bordage S, Pudlo M, Demougeot C, Thai KM, Girard-Thernier C. Cinnamide derivatives as mammalian arginase inhibitors: synthesis, biological evaluation and molecular docking. Int J Mol Sci 2016;17:1656CrossRefGoogle Scholar
  51. 51.
    Shin W, Cuong TD, Lee JH, Min B, Jeon BH, Lim HK, et al. Arginase inhibition by ethylacetate extract of Caesalpinia sappan lignum contributes to activation of endothelial nitric oxide synthase. Korean J Physiol Pharmacol. 2011;15:123–8.CrossRefGoogle Scholar
  52. 52.
    JS Z. L L, FY C. Tetrahydrobiopterin and vascular endothelial dysfunction. Prog Physiol Sci. 2004;35:155–8.Google Scholar
  53. 53.
    Antoniades C, Bakogiannis C, Leeson P, Guzik TJ, Zhang MH, Tousoulis D, et al. Rapid, direct effects of statin treatment on arterial redox state and nitric oxide bioavailability in human atherosclerosis via tetrahydrobiopterin-mediated endothelial nitric oxide synthase coupling. Circulation. 2011;124:335–45.CrossRefGoogle Scholar
  54. 54.
    Herranz B, Marquez S, Guijarro B, Aracil E, Aicart-Ramos C, Rodriguez-Crespo I, et al. Integrin-linked kinase regulates vasomotor function by preventing endothelial nitric oxide synthase uncoupling: role in atherosclerosis. Circ Res. 2012;110:439–49.CrossRefGoogle Scholar
  55. 55.
    Zhou MM. Protective effect and mechanism of propofol on endothelial injury induced by high glucose. Shanghai: Fudan University; 2012.Google Scholar
  56. 56.
    Liu JB, Wang G, Hong TP. Fenofibrate promotes endothelial nitric oxide synthase coupling by up regulating the level of four hydrogen biopterin. In: Annual meeting of endocrinology and diabetes branch of Beijing Medical Association. 2011.Google Scholar
  57. 57.
    Zhang HP. Vasodilatation effect and anti eNOS coupling mechanism of 7 Chinese herbal extracts. Thesis, Shanghai university of Chinese medicine. 2010.Google Scholar
  58. 58.
    Hofmeister LH, Lee SH, Norlander AE, Montaniel KR, Chen W, Harrison DG, et al. Phage-display-guided nanocarrier targeting to atheroprone vasculature. ACS Nano. 2015;9:4435–46.CrossRefGoogle Scholar
  59. 59.
    Li H, Forstermann U. Uncoupling of endothelial NO synthase in atherosclerosis and vascular disease. Curr Opin Pharmacol. 2013;13:161–7.CrossRefGoogle Scholar
  60. 60.
    Bhardwaj P, Khanna D, Balakumar P. Catechin averts experimental diabetes mellitus-induced vascular endothelial structural and functional abnormalities. Cardiovasc Toxicol. 2014;14:41–51.CrossRefGoogle Scholar
  61. 61.
    Jung CH, Lee WJ, Hwang JY, Lee MJ, Seol SM, Kim YM, et al. The preventive effect of uncarboxylated osteocalcin against free fatty acid-induced endothelial apoptosis through the activation of phosphatidylinositol 3-kinase/Akt signaling pathway. Metabolism. 2013;62:1250–7.CrossRefGoogle Scholar
  62. 62.
    CM W. H L, JY W. The mechanism of berberine regulating eNOS/NO to protect HUVECs damage induced by palmitic acid. J Beihua Univ (Nat Sci). 2014;15:743–6.Google Scholar
  63. 63.
    Go YM, Lee HR, Park H. H(2)S inhibits oscillatory shear stress-induced monocyte binding to endothelial cells via nitric oxide production. Mol Cells. 2012;34:449–55.CrossRefGoogle Scholar
  64. 64.
    LJ LL. Z. Hydrogen sulfide: a new target for atherosclerosis research Chinese. J Arterioscler. 2015;23:201–6.Google Scholar
  65. 65.
    Li W, Tang C, Jin H, Du J. Effects of onion extract on endogenous vascular H2S and adrenomedulin in rat atherosclerosis. Curr Pharm Biotechnol. 2011;12:1427–39.CrossRefGoogle Scholar
  66. 66.
    Hayashi T, Yamaguchi T, Sakakibara Y, Taguchi K, Maeda M, Kuzuya M, et al. eNOS-dependent antisenscence effect of a calcium channel blocker in human endothelial cells. PLoS One. 2014;9:e88391.CrossRefGoogle Scholar
  67. 67.
    Liu SJ, Liu WH, Zhong Y, Liu SM. Glycogen synthase kinase-3beta is involved in C-reactive protein-induced endothelial cell activation. Biochemistry. 2013;78:915–9.Google Scholar
  68. 68.
    da Motta NA, Kummerle AE, Marostica E, Dos Santos CF, Fraga CA, Barreiro EJ, et al. Anti-atherogenic effects of a new thienylacylhydrazone derivative, LASSBio-788, in rats fed a hypercholesterolemic diet. J Pharmacol Sci. 2013;123:47–57.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Physiology, College of MedicineNanchang UniversityNanchangChina

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