Yarmysh N. V., Grozna L. N.

Endothelial Dysfunction and its Regulatory Factors

About the author:

Yarmysh N. V., Grozna L. N.



Type of article:

Scentific article


Endothelial dysfunction (ED) is an imbalance between the production of vasodilating, angioprotect­ ing, antiproliferative factors on the one hand and that of vasoconstrictive, prothrombotic and proliferative factors on the other hand. In different vascular diseases and metabolic disturbances the ability of ED to release relaxing factors reduces, whereas the formation of vasoconstrictive factors maintains or increases, resulting in endothelial dysfunction. An imbalance of NO production against a background of an increased production of reactive forms of oxygen can initiate ED. NO plays the key protective role in the development of coronary atherosclerosis. Its release is potentiated by: circulating hormones, thrombocyte products, histamine, bradykinin, etc. NO prevents pathologi­ cal vasospasm of coronary arteries, inhibits aggregation of thrombocytes and expression of endothelial molecules of adhesion, inhibiting penetration of macrophages. Disruption of the protective function of NO results in the devel­ opment of an inflammatory response with subsequent atherosclerosis. Particularly important for the development of ED is sirtuin 1 (SIRT1), which regulates the activity of eNOS. Its physiological effects are realized via SIRT1­dependent diacetylation of substrates. Representatives of FOXOs branch, which produce their effect on manganese­dependent superoxide dismutase (MnSOD) and expression of the gene of the protein that is responsible for growth arrest and damage of DNA (GADD45), serve as targets for SIRT1. Other SIRT1 substrates are represented by peroxisome proliferator­activated receptors gamma and alpha (PPAR­γ and PPARα) and coactivator 1­alpha (PGC­1α), AMP­activated protein kinase (AMPK), tumour suppressor protein p53, nuclear factor kB (NF­kB) and eNOS. The effects of regulation of these signalling pathways under the influence of SIRT1 result in protection of cardiomyocytes and endothelial cells (EC), balance of lipid metabolism, inhibition of inflammation and formation of atherosclerotic plaques, and delay of cardiac hypertrophy. The activa­ tion of SIRT1 helps to restore eNOS activity in ED, when NO accessibility is restricted, and prevents hypertrophy of vascular smooth muscle cells (SMC), which is considered to be one of accompanying components of atherosclero­ sis. SIRT1 expression also prevents angiotensin II­induced hypertrophy of vascular SMC. Positive effects on SIRT1 metabolism are produced by a hypocaloric diet, resveratrol and cilostazol. Resve­ ratrol stimulates SIRT1 activity, activates eNOS, improves the endothelial function, prevents an elevation in blood pressure and restores the vascular activity of eNOS in animal models of ED. The use of Resveratrol also prevents concentric hypertrophy and cardiac dysfunction. Resveratrol eliminates oxidative stress­induced proliferation of coronary SMC by inhibition of kinase. Cilostazol inhibits oxidative stress­induced damages, increasing SIRT1 expression in human EC in vitro and in vivo. Cilostazol decreases acetylation of p53 via lysine residues in SIRT1 targets. Nevertheless, the protective ef­ fects of SIRT1 can be mediated by other SIRT1 targets, which influence the biology of EC. Cilostazol activates eNOS via cAMP/PKA­ and PI3K/Akt­dependent pathways via induction of eNOS phosphorylation via Ser1177, increases mRNA and expression of SIRT1 protein, which stimulates NO formation under the influence of eNOS. These data confirm that SIRT1­activating drug preparations can produce protective effects on vascular endothelium; this phe­ nomenon can become the subject of further studies


endothelial dysfunction, endothelial nitric oxide synthase (еNOS), sirtuin 1 (SIRT1), obesity, arterial hypertension, diabetes mellitus


  1. адашева т. В. NO и сердечно­сосудистая патология / т. В. адашева // Электронный журнал ANGIOLOGIA. ru – № 1 / 2010.
  2. кузьминова н. В. Функциональное состояние сосудистого эндотелия у больных гипертонической болезнью / н. В. кузьминова, В. к. серкова // український терапевтичний журнал. – 2008. – № 2. – с. 21­27.
  3. леженко г. а. Факторы формирования артериальной гипертензии у детей с ожирением / г. а. леженко, к. В. гладун, е. е. пашкова // дітячий лікар. – 2011. – № 3. – с. 23­34.
  4. лупинская з. а. Эндотелий: функция и дисфункция / з. а. лупинская, а. г. зарифьян, т. Ц. гурович, с. г. Шлейфер. – б.: крсу, 2008. – 373 c.
  5. Шишкин а. н. Эндотелиальная дисфункция и артериальная гипертензия / а. н. Шишкин, М. л. лындина // артериаль­ ная гипертензия 2008. – т. 14, № 4. – с. 315­319.
  6. Шмидт е. а. роль факторов воспаления и маркеров эндотелиальной дисфункции у больных острым коронарным синдромом с подъемом сегмента ST в профилактике развития неблагоприятных исходов / е. а. Шмидт, с. а. бернс, е. с. киприна [и др.] // кардиоваскуляр. терапия и профилактика. – 2008. – т. 7, № 6 (прил. 1). – с. 14­15.
  7. Campia U. Human obesity and endothelium­dependent responsiveness / U. Campia, М. Tesauro, с. Cardillo // British Journal of Pharmacology. – 2012. – Vol. 165. – P. 561–573.
  8. Cardellini M. TIMP3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SirT1 / M. Car­ dellini, R. Menghini, E. Martelli [et al.] // Diabetes. – 2009. – Vol. 58. – P. 2396­2401.
  9. Casas J. P. Endotelial nitric oxide syntase gene polymorphisms and cardiovascular disease: a HuGE review / J. P. Casas, G. L. Cavalleri, L. E. Bautista [et al.] // American J. Human genome epidemiology. – 2006. – Vol. 17. – P. 1­15.
  10. Cooke J. P. ADMA: its role in vascular disease / J. P. Cooke // Vasc. Med. – 2005. – Vol. 10(Suppl 1). – P. S11–S17.
  11. Corretti M. C. Guidelines for the ultrasound assesment of endotelin­dependent flow­mediated vasodilation of the brachial artery reactivity / M. C. Corretti, T. J. Anderson, F. J. Beniamin [et al.] // J. Amer. Coll. Cardiol. – 2002. – Vol. 39. – P. 257­265.
  12. Dahlof B. Cardiovascular morbidity and mortality in the Losartan Intervention for End pointreduction in hypertension study (LIFE): arandomized trial against atenolol / B. Dahlof, R. B. Devereux, S. E. Kjeldsen [et al.] // Lancet. – 2002. – Vol. 359. – P. 995–1003.
  13. El Assar M. Mechanisms involved in the aging­induced vascular dysfunction / M. El Assar, J. Angulo, S. Vallejo [et al.] // Front Physiol. – 2012. – Vol. 3. – P. 132.
  14. Hughes K. J. FoxO1 and SIRT­1 Regulate β­Cell Responses to Nitric Oxide / K. J. Hughes, G. P. Meares, P. A. Hansen [et al.] // The journal of biological chemistry. – 2011. – Vol. 286, № 10. – р. 8338–8348.
  15. Higashi Y. Endothelial function and oxidative stress in cardiovascular diseases / Y. Higashi, K. Noma, M. Yoshizumi, [et al.] // Circ. J. – 2009. – Vol. 73 (3). – P. 411­418.
  16. Junlan Zhou. аdipocytes dysfunction and hypertension / Zhou Junlan, Qin Gangjian // Am. J. Cardiovasc. Dis. – 2012. – Vol. 2(2). – р. 143­149.
  17. Garaliene V. Endothelium and nitric oxide / V. Garaliene // Medicina (Kaunas). – 2008. – Vol. 44. – P. 564–569.
  18. Greenstein A. S. Local inflammation and hypoxia abolish the protective anticontractile properties of perivascular fat in obese patients / A. S. Greenstein, K. Khavandi, S. B. Withers, [et al.] // Circulation. – 2009. – Vol. 119. – P. 1661–1670.
  19. Kelly G. S. A review of the sirtuin system, its clinical implications, and the potential role of dietary activations like resveratrol: part 2 / G. S. Kelly // Alternative medicine review. – 2010. – Vol. 15, № 4. – P. 313­328.
  20. Kim J. A Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms / J. A. Kim, M. Montagnani, K. K. Koh [et al.] // Circulation. – 2006. – Vol. 113. – P. 1888–1904.
  21. Luo J. Negative control of p53 by Sir2alpha promotes cell survival under stress / J. Luo, A. Y. Nikolaev, S. Imai, [et al.] // Cell. – 2001. – Vol. 107. – P. 137–148.
  22. Lund D. D. Gene transfer of endothelial nitric oxide synthase improves relaxation of carotid arteries from diabetic rabbits / D. D. Lund, F. M. Faraci, F. J. Jr. Miller [et al.] // Circulation. – 2000. – Vol. 101. – P. 1027–1033.
  23. Mattagajasingh I. SIRT1 promotes endothelium­dependent vascular relaxation by activating endothelial nitric oxide synthase / I. Mattagajasingh, Cuk­Seong Kim, Asma Naqvi [et al.] // PNAS. – 2007. – Vol. 104, № 37. – P. 14855–14860.
  24. Mather K. J. Interactions between endothelin and nitric oxide in the regulation of vascular tone in obesity and diabetes / K. J. Mather, A. Lteif, H. O. Steinberg [et al.] // Diabetes. – 2004. – Vol. 53. – P. 2060–2066.
  25. Meininger C. J. Impaired nitric oxide production in coronary endothelial cells of the spontaneously diabetic BB rat is due to tetrahydrobiopterin deficiency / C. J. Meininger, S. Cai, J. L. Parker [et al.] // Biochem J. – 2000. – Vol. 349. – P. 353–356.
  26. Muniyappa R. An integrated view of insulin resistance and endothelial dysfunction / R. Muniyappa, M. Iantorno, M. J. Quon // Endocrinol. Metab. Clin. North. Am. – 2008. – Vol. 37. – P. 685–711.
  27. Nakagawa T. Sirtuins at a glance / T. Nakagawa, L. Guarente // Journal of Cell Science. – 2011. – Vol. 124 (6). – р. 833­838.
  28. Oak J. H. Attenuation of angiotensin II signaling recouples eNOS and inhibits non endothelial NOS activity in diabetic mice / J. H. Oak, H. Cai // Diabetes. – 2007. – Vol. 56. – P. 118–126.
  29. Ohsawa M. RhoA/Rho kinase pathway contributes to the pathogenesis of thermal hyperalgesia in diabetic mice / M. Ohsawa, M. Aasato, S. S. Hayashi [et al.] // Pain. – 2011. – Vol. 152. – P. 114–122.
  30. Ota H. Cilostazol inhibits oxidative stress­induced premature senescence via upregulation of Sirt1 in human endothelial cells / H. Ota, M. Eto, M. R. Kano [et al.] // Arterioscler. Thromb. Vasc. Biol. – 2008. – Vol. 28. – P. 1634 –1639.
  31. Potente M. NO Targets SIRT1: A Novel Signaling Network in Endothelial Senescence / M. Potente, S. Dimmeler // Arterioscler. Thromb. Vasc. Biol. – 2008. – Vol. 28. – P. 1577­1579.
  32. Puca A. A. Endothelial nitric oxide synthase, vascular integrity and human exceptional longevity / A. A. Puca, A. Carrizzo, A. Ferrario [et al.] // Immunity & Ageing. – 2012. – Vol. 9. – P. 26.
  33. Rippe C. Short­term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress / C. Rippe, L. Lesniewski, M. Connell [et al.] // Aging. Cell. – 2010. – Vol. 9. – P. 304–312.
  34. Romero M. J. Diabetes­induced coronary vascular dysfunction involves increased arginase activity / M. J. Romero, D. H. Platt, H. E. Tawfik [et al.] // Circ. Res. – 2008. – Vol. 102. – P. 95–102.
  35. Tanno M. Induction of manganese superoxide dismutase by nuclear translocation and activation of SIRT1 promotes cell sur­ vival in chronic heart failure / M. Tanno, A. Kuno, T. Yano [et al.] // J. Biol. Chem. – 2010. – Vol. 285(11). – P. 8375–8382.
  36. Tesauro M. Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity­related metabolic syndrome / M. Tesauro, F. Schinzari, V. Rovella [et al.] // Hypertension. – 2009. – Vol. 54. – P. 995–1000.
  37. Thandapilly S. J. Resveratrol prevents the development of pathological cardiac hypertrophy and contractile dysfunction in the SHR without lowering blood pressure / S. J. Thandapilly, P. Wojciechowski, J. Behbahani [et al.] // Am. J. Hypertens. – 2010. – Vol. 23(2). – P. 192–196.
  38. Vasamsetti S. B. Oxidative stress­induced vascular dysfunction: mechanistic perspectives and preventive strategies / S. B. Vasamsetti, S. Kotamraju // IIOABJ. – 2011. – Vol. 2; Issue 6. – р. 9–28.
  39. Vanhoutte P. M. Endothelial dysfunction: the first step toward coronary arteriosclerosis / P. M. Vanhoutte // Circ. J. – 2009. – Vol. 73 (4). – P. 595­601.
  40. Wenzel P. Mechanisms underlying recoupling of eNOS by HMG­CoA reductase inhibition in a rat model of streptozotocin­ induced diabetes mellitus / P. Wenzel, A. Daiber, M. Oelze [et al.] // Atherosclerosis. – 2008. – Vol. 198. – P. 65–76.
  41. 41. Xu J. Tyrosine nitration of PA700 activates the 26S proteasome to induce endothelial dysfunction in mice with angiotensin II­induced hypertension/J. Xu, S. Wang, Y. Wu, [et al.]// Hypertension. – 2009. – Vol. 54. – P. 625–632.
  42. Zhao Zhong Chong. Targeting Cardiovascular Disease with Novel SIRT­1 Pathways / Zhao Zhong Chong, Shaohui Wang, Yan Chen Shang, Kenneth Maiese // Future Cardiol. ­ 2012. – Vol. 8(1). – р. 89–100.
  43. Zhang Q. J. Endothelium­specific overexpression of class III deacetylase SIRT1 decreases atherosclerosis in apolipoprotein E­deficient mice / Q. J. Zhang, Z. Wang, H. Z. Chen [et al] // Cardiovasc. Res. – 2008. – Vol. 80(2). – P. 191–199.
  44. Zhou G. Role of AMP­activated protein kinase in mechanism of metformin action / G. Zhou, R. Myers, Y. Li [et al.] // J. Clin. Invest. – 2001. – Vol. 108. – P. 1167–1174.

Publication of the article:

«Bulletin of problems biology and medicine» Issue 3 part 2 (111), 2014 year, 37-43 pages, index UDK 611­018. 26:575. 191