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Archives of Medical Science
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vol. 14
Basic research

Apelin/APJ axis improves angiotensin II-induced endothelial cell senescence through AMPK/SIRT1 signaling pathway

Rongfeng Yang, Wu Fang, Jiawen Liang, Chao Lin, Shaoyun Wu, Shaodi Yan, Chengheng Hu, Xiao Ke

Arch Med Sci 2018; 14, 4: 725–734
Online publish date: 2017/09/26
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Previous studies have shown that endothelial cell senescence is involved in cardiovascular diseases such as cardiac fibrosis, atherosclerosis and heart failure. Accumulating evidence indicates that apelin exerts protective effects on ageing-related endothelial dysfunction. In this study, we aim to investigate the role of the apelin/APJ axis in angiotensin II (AngII)-induced endothelium senescence and its associated mechanisms.

Material and methods
Senescence-related β-gal activity assay and western blot were used to evaluate human umbilical vein endothelial cell (HUVEC) senescence. In addition, DCFH-DA staining was carried out to detect the generation of reactive oxygen species (ROS). A validated, high-sensitivity real-time quantitative telomeric repeat amplification protocol (RQ-TRAP) was applied to determine telomerase activity in HUVECs, and a CCK-8 assay was employed to measure cellular viability.

AngII induced an increase in SA-β-Gal-positive cells and upregulation on expression of P21 and PAI-1 compared to the control group (p < 0.05), while apelin against this process (p < 0.05). The protective effects were attenuated when APJ, AMPK and SIRT1 expression was knocked down (p < 0.05). Furthermore, apelin reduced AngII-induced ROS generation and enhanced telomerase activity in HUVECs (p < 0.05), which contributed to increased HUVEC viability as assessed by the CCK-8 assay (p < 0.05).

The apelin/APJ axis improved AngII-induced HUVEC senescence via the AMPK/SIRT1 signaling pathway, and the underlying mechanisms might be associated with reduced ROS production and enhanced telomerase activity.


apelin, endothelium, senescence, mechanisms

Barodka VM, Joshi BL, Berkowitz DE, Hogue CW Jr, Nyhan D. Review article: implications of vascular aging. Anesthesia Analgesia 2011; 112: 1048-60.
Tao J, Jin YF, Yang Z, et al. Reduced arterial elasticity is associated with endothelial dysfunction in persons of advancing age: comparative study of noninvasive pulse wave analysis and laser Doppler blood flow measurement. Am J Hypertens 2004; 17: 654-9.
Taddei S, Virdis A, Mattei P, et al. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation 1995; 91: 1981-7.
Virdis A, Ghiadoni L, Giannarelli C, Taddei S. Endothelial dysfunction and vascular disease in later life. Maturitas 2010; 67: 20-4.
Tatemoto K, Hosoya M, Habata Y, et al. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun 1998; 251: 471-6.
Yang S, Li H, Tang L, et al. Apelin-13 protects the heart against ischemia-reperfusion injury through the
RISK-GSK-3beta-mPTP pathway. Arch Med Sci 2015; 11: 1065-73.
Lee DK, Ferguson SS, George SR, O’Dowd BF. The fate of the internalized apelin receptor is determined by different isoforms of apelin mediating differential interaction with beta-arrestin. Biochem Biophys Res Commun 2010; 395: 185-9.
Momiyama Y. Association between plasma apelin levels and coronary collateral development in patients with stable angina pectoris. Atherosclerosis 2014; 235: 349-50.
Novakova V, Sandhu GS, Dragomir-Daescu D, Klabusay M. Apelinergic system in endothelial cells and its role in angiogenesis in myocardial ischemia. Vascul Pharmacol 2016; 76: 1-10.
Huang S, Chen L, Lu L, Li L. The apelin-APJ axis: a novel potential therapeutic target for organ fibrosis. Clin Chim Acta 2016; 456: 81-8.
Chong KS, Gardner RS, Morton JJ, Ashley EA, McDonagh TA. Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. Eur J Heart Fail 2006; 8: 355-60.
Francia P, Salvati A, Balla C, et al. Cardiac resynchronization therapy increases plasma levels of the endogenous inotrope apelin. Eur J Heart Fail 2007; 9: 306-9.
Minamino T, Miyauchi H, Yoshida T, Tateno K, Kunieda T, Komuro I. Vascular cell senescence and vascular aging. J Mol Cell Cardiol 2004; 36: 175-83.
Maizel J, Vasko R, Xavier S, Chen J, Cao J, Goligorsky MS. Vascular senescence and organ fibrosis. Proceedings of the Physiological Society 2013; Proc 37th IUPS.
Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H, Komuro I. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation 2002; 105: 1541-4.
Lee D, Cheng R, T, Fan T, et al. Characterization of apelin, the ligand for the APJ receptor. J Neurochem 2000; 74: 34-41.
Li P, Guo X, Lei P, Shi S, Luo S, Cheng X. PI3K/Akt/uncoupling protein 2 signaling pathway may be involved in cell senescence and apoptosis induced by angiotensin II in human vascular endothelial cells. Mol Biol Rep 2014; 41: 6931-7.
Mikhed Y, Daiber A, Steven S. Mitochondrial oxidative stress, mitochondrial DNA damage and their role in age-related vascular dysfunction. Int J Mol Sci 2015; 16: 15918-53.
Minamino T, Komuro I. Role of telomere in endothelial dysfunction in atherosclerosis. Curr Opin Lipidol 2002; 13: 537-43.
Huang F, Thompson JC, Wilson PG, Aung HH, Rutledge JC, Tannock LR. Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development. J Lipid Res 2008; 49: 521-30.
Siddiquee K, Hampton J, Khan S, et al. Apelin protects against angiotensin II-induced cardiovascular fibrosis and decreases PAI-1 production. J Hypertens 2011; 29: 724-31.
Chun HJ, Ali ZA, Kojima Y, et al. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J Clin Investig 2008; 118: 3343-54.
Pallottini V, Montanari L, Cavallini G, Bergamini E, Gori Z, Trentalance A. Mechanisms underlying the impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in aged rat liver. Mech Ageing Dev 2004; 125: 633-9.
Gonzalez AA, Kumar R, Mulligan JD, Davis AJ, Saupe KW. Effects of aging on cardiac and skeletal muscle AMPK activity: basal activity, allosteric activation, and response to in vivo hypoxemia in mice. Am J Physiol Regul Integr Comp Physiol 2004; 287: R1270.
Mulligan JD, Gonzalez AA, Kumar R, Davis AJ, Saupe KW. Aging elevates basal adenosine monophosphate-activated protein kinase (AMPK) activity and eliminates hypoxic activation of AMPK in mouse liver. J Gerontol 2005; 60: 21-7.
Reznick RM, Zong H, Li J, et al. Aging-associated reductions in AMP-activated protein kinase activity and mitochondrial biogenesis. Cell Metabol 2007; 5: 151-6.
Pchejetski D, Foussal C, Alfarano C, et al. Apelin prevents cardiac fibroblast activation and collagen production through inhibition of sphingosine kinase 1. Eur Heart J 2012; 33: 2360-9.
Guarente L. Sirtuins, aging, and medicine. N Engl J Med 2011; 364: 2235-44.
Wilson SK. Role of oxygen-derived free radicals in acute angiotensin II: induced hypertensive vascular disease in the rat. Circ Res 1990; 66: 722-34.
Ushiofukai M, Zafari AM, Fukui T, Ishizaka N, Griendling KK. p22phox Is a critical component of the superoxide-generating NADH/NADPH oxidase system and regulates angiotensin II-induced hypertrophy in vascular smooth muscle cells. J Biol Chem 1996; 271: 23317-21.
Adelibieke Y, Shimizu H, Muteliefu G, Bolati D, Niwa T. Indoxyl sulfate induces endothelial cell senescence by increasing reactive oxygen species production and p53 activity. J Renal Nutrition 2012; 22: 86-9.
Yang J, Chang E, Cherry AM, et al. Human endothelial cell life extension by telomerase expression. J Biol Chem 1999; 274: 26141-8.
Vasa M, Breitschopf K, Zeiher AM, Dimmeler S. Nitric oxide activates telomerase and delays endothelial cell senescence. Circ Res 2000; 87: 540-2.
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