Abstract
The anti-senescence activity of genistein is associated with inducing autophagy; however, the underlying mechanisms are not fully understood. In this study, human umbilical vein endothelial cells (HUVECs) were pretreated with genistein (1000 nM) for 30 min and then exposed to ox-LDL (50 mg/L) for another 12 h. The study found that genistein inhibited the ox-LDL-induced senescence (reducing the levels of P16 and P21 protein, and the activity of SA-β-gal); meanwhile, the effect of genistein was bound up with enhancing autophagic flux (increasing LC3-II, and decreasing the level of P62, p-mTOR and p-P70S6K). Moreover, SIRT1/LKB1/AMPK pathway was involved in genistein accelerating autophagic flux and mitigating senescence in HUVECs. The present study illustrated that genistein was a promising therapeutic agent to delay aging process and extend longevity.
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Martins MJ, Constância M, Neves D, Simm A (2017) Biomarkers of aging: from cellular senescence to age-associated diseases. Oxid Med Cell Longev 2017:7280690
de Almeida AJPO, Ribeiro TP, de Medeiros IA (2017) Aging: molecular pathways and implications on the cardiovascular system. Oxid Med Cell Longev. https://doi.org/10.1155/2017/7941563
Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG (2017) The aging cardiovascular system: understanding it at the cellular and clinical levels. J Am Coll Cardiol 69(15):1952–1967
Ashapkin VV, Kutueva L, Vanyushin BF (2017) Aging as an epigenetic phenomenon. Curr Genom 18(5):385–407
Donato AJ, Morgan RG, Walker AE, Lesniewski LA (2015) Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol 89:122–135
Regina C, Panatta E, Candi E, Melino G, Amelio I, Balistreri CR, Annicchiarico-Petruzzelli M, Di Daniele N, Ruvolo G (2016) Vascular ageing and endothelial cell senescence: molecular mechanisms of physiology and diseases. Mech Ageing Dev 159:14–21
Mialet-Perez J, Vindis C (2017) Autophagy in health and disease: focus on the cardiovascular system. Essays Biochem 61(6):721–732
Tai H, Wang Z, Gong H, Han X, Zhou J, Wang X, Wei X, Ding Y, Huang N, Qin J, Zhang J, Wang S, Gao F, Chrzanowska-Lightowlers ZM, Xiang R, Xiao H (2017) Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence. Autophagy 13(1):99–113
Ibrahim NH, Thandapilly SJ, Jia Y, Netticadan T, Aukema H (2016) Soy protein alleviates hypertension and fish oil improves diastolic heart function in the Han: SPRD-Cy rat model of cystic kidney disease. Lipids 51(5):635–642
Si H, Liu D (2014) Dietary antiaging phytochemicals and mechanisms associated with prolonged survival. J Nutr Biochem 25(6):581–591
Zhang HP, Zhao JH, Yu HX, Guo DX (2016) Genistein ameliorated endothelial nitric oxidase synthase uncoupling by stimulating sirtuin-1 pathway in ox-LDL-injured HUVECs. Environ Toxicol Pharmacol 42:118–124
Zhang H, Zhao Z, Pang X, Yang J, Yu H, Zhang Y, Zhou H, Zhao J (2017) MiR-34a/sirtuin-1/foxo3a is involved in genistein protecting against ox-LDL-induced oxidative damage in HUVECs. Toxicol Lett 277:115–122
Kida Y, Goligorsky MS (2016) Sirtuins, cell senescence, and vascular aging. Can J Cardiol 32(5):634–641
Kitada M, Ogura Y, Koya D (2016) The protective role of Sirt1 in vascular tissue: its relationship to vascular aging and atherosclerosis. Aging 8(10):2290–2307
Bai B, Man AW, Yang K, Guo Y, Xu C, Tse HF, Han W, Bloksgaard M, De Mey JG, Vanhoutte PM, Xu A, Wang Y (2016) Endothelial SIRT1 prevents adverse arterial remodeling by facilitating HERC2-mediated degradation of acetylated LKB1. Oncotarget 7(26):39065–39081
Ganesan R, Hos NJ, Gutierrez S, Fischer J, Stepek JM, Daglidu E, Krönke M, Robinson N (2017) Salmonella typhimurium disrupts Sirt1/AMPK checkpoint control of mTOR to impair autophagy. PLoS Pathog 13(2):e1006227
Cetrullo S, D’Adamo S, Tantini B, Borzi RM, Flamigni F (2015) mTOR, AMPK, and Sirt1: key players in metabolic stress management. Crit Rev Eukaryot Gene Expr 25(1):59–75
Lan F, Cacicedo JM, Ruderman N, Ido Y (2008) SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 283(41):27628–27635
Li GH, Lin XL, Zhang H, Li S, He XL, Zhang K, Peng J, Tang YL, Zeng JF, Zhao Y, Ma XF, Lei JJ, Wang R, Wei DH, Jiang ZS, Wang Z (2015) Ox-Lp(a) transiently induces HUVEC autophagy via an ROS-dependent PAPR-1-LKB1-AMPK-mTOR pathway. Atherosclerosis 243(1):223–235
Wang B, Yang Q, Sun YY, Xing YF, Wang YB, Lu XT, Bai WW, Liu XQ, Zhao YX (2014) Resveratrol-enhanced autophagic flux ameliorates myocardial oxidative stress injury in diabetic mice. J Cell Mol Med 18(8):1599–1611
Park SY, Le HR, Lee WS, Shin HK, Kim HY, Hong KW, Kim CD (2016) Cilostazol modulates autophagic degradation of β-amyloid peptide via SIRT1-coupled LKB1/AMPKα signaling in neuronal cells. PLoS ONE 11(8):e0160620
Lee KY, Kim JR, Choi HC (2016) Genistein-induced LKB1-AMPK activation inhibits senescence of VSMC through autophagy induction. Vascul Pharmacol 81:75–82
Camici GG, Savarese G, Akhmedov A, Lüscher TF (2015) Molecular mechanism of endothelial and vascular aging: implications for cardiovascular disease. Eur Heart J 36(48):3392–3403
Guo Y, Xu A, Wang Y (2016) SIRT1 in endothelial cells as a novel target for the prevention of early vascular aging. J Cardiovasc Pharmacol 67(6):465–473
Iop L, Dal Sasso E, Schirone L, Forte M, Peruzzi M, Cavarretta E, Palmerio S, Gerosa G, Sciarretta S, Frati G (2017) The light and shadow of senescence and inflammation in cardiovascular pathology and regenerative medicine. Mediat Inflamm. https://doi.org/10.1155/2017/7953486
Ming GF, Tang YJ, Hu K, Chen Y, Huang WH, Xiao J (2016) Visfatin attenuates the ox-LDL-induced senescence of endothelial progenitor cells by upregulating SIRT1 expression through the PI3K/Akt/ERK pathway. Int J Mol Med 38(2):643–649
Sun L, Dou F, Chen J, Chi H, Xing S, Liu T, Sun S, Chen C (2018) Salidroside slows the progression of EA.hy926 cell senescence by regulating the cell cycle in an atherosclerosis model. Mol Med Rep 17(1):257–263
Antikainen H, Driscoll M, Haspel G, Dobrowolski R (2017) TOR-mediated regulation of metabolism in aging. Aging Cell 16(6):1219–1233
Henning RH, Brundel BJJM (2017) Proteostasis in cardiac health and disease. Nat Rev Cardiol 14(11):637–653
de Meyer GR, Grootaert MO, Michiels CF, Kurdi A, Schrijvers DM, Martinet W (2015) Autophagy in vascular disease. Circ Res 116(3):468–479
Yin Z, Pascual C, Klionsky DJ (2016) Autophagy: machinery and regulation. Microb Cell 3(12):588–596
Mizushima N, Yoshimori T (2007) How to interpret LC3 immunoblotting. Autophagy 3(6):542–545
Kim JH, Lee SJ, Kim KW, Yu YS, Kim JH (2012) Oxidized low density lipoprotein-induced senescence of retinal pigment epithelial cells is followed by outer blood-retinal barrier dysfunction. Int J Biochem Cell Biol 44(5):808–814
Zhang JJ, Liu WQ, Peng JJ, Ma QL, Peng J, Luo XJ (2017) miR-21-5p/203a-3p promote ox-LDL-induced endothelial cell senescence through down-regulation of mitochondrial fission protein Drp1. Mech Ageing Dev 164:8–19
Maiese K (2016) Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br J Clin Pharmacol 82(5):1245–1266
Perl A (2015) mTOR activation is a biomarker and a central pathway to autoimmune disorders, cancer, obesity, and aging. Ann N Y Acad Sci 1346(1):33–44
Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A (2013) Antagonistic crosstalk between NF-kB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal 25(10):1939–1948
Jeon SM (2016) Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48(7):e245
Lan F, Weikel KA, Cacicedo JM, Ido Y (2017) Resveratrol-induced AMP-activated protein kinase activation is cell-type dependent: lessons from basic research for clinical application. Nutrients 9(7):E751
Velagapudi R, El-Bakoush A, Lepiarz I, Ogunrinade F, Olajide OA (2017) AMPK and SIRT1 activation contribute to inhibition of neuroinflammation by thymoquinone in BV2 microglia. Mol Cell Biochem 435:149–162
Wang S, Wang Y, Zhang Z, Liu Q, Gu J (2017) Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway. Cell Death Dis 8(8):e3018
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This work was supported by the National Natural Science Foundation of China (No. 31000481), and the Natural Science Foundation of Shanxi Province, China (No. 2011011040-2).
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Zhang, H., Yang, X., Pang, X. et al. Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/LKB1/AMPK-mediated autophagy flux in HUVECs. Mol Cell Biochem 455, 127–134 (2019). https://doi.org/10.1007/s11010-018-3476-8
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DOI: https://doi.org/10.1007/s11010-018-3476-8