Skip to main content
SpringerLink
Log in

Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/LKB1/AMPK-mediated autophagy flux in HUVECs

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. 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

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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

    Article  PubMed  Google Scholar 

  4. Ashapkin VV, Kutueva L, Vanyushin BF (2017) Aging as an epigenetic phenomenon. Curr Genom 18(5):385–407

    Article  CAS  Google Scholar 

  5. Donato AJ, Morgan RG, Walker AE, Lesniewski LA (2015) Cellular and molecular biology of aging endothelial cells. J Mol Cell Cardiol 89:122–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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

    Article  CAS  PubMed  Google Scholar 

  7. Mialet-Perez J, Vindis C (2017) Autophagy in health and disease: focus on the cardiovascular system. Essays Biochem 61(6):721–732

    Article  PubMed  Google Scholar 

  8. 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

    Article  CAS  PubMed  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. Si H, Liu D (2014) Dietary antiaging phytochemicals and mechanisms associated with prolonged survival. J Nutr Biochem 25(6):581–591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Kida Y, Goligorsky MS (2016) Sirtuins, cell senescence, and vascular aging. Can J Cardiol 32(5):634–641

    Article  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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

    PubMed  PubMed Central  Google Scholar 

  16. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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

    Article  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee KY, Kim JR, Choi HC (2016) Genistein-induced LKB1-AMPK activation inhibits senescence of VSMC through autophagy induction. Vascul Pharmacol 81:75–82

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. 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

    Article  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. 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

    CAS  PubMed  Google Scholar 

  28. Antikainen H, Driscoll M, Haspel G, Dobrowolski R (2017) TOR-mediated regulation of metabolism in aging. Aging Cell 16(6):1219–1233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Henning RH, Brundel BJJM (2017) Proteostasis in cardiac health and disease. Nat Rev Cardiol 14(11):637–653

    Article  CAS  PubMed  Google Scholar 

  30. de Meyer GR, Grootaert MO, Michiels CF, Kurdi A, Schrijvers DM, Martinet W (2015) Autophagy in vascular disease. Circ Res 116(3):468–479

    Article  CAS  PubMed  Google Scholar 

  31. Yin Z, Pascual C, Klionsky DJ (2016) Autophagy: machinery and regulation. Microb Cell 3(12):588–596

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mizushima N, Yoshimori T (2007) How to interpret LC3 immunoblotting. Autophagy 3(6):542–545

    Article  CAS  PubMed  Google Scholar 

  33. 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

    Article  CAS  PubMed  Google Scholar 

  34. 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

    Article  CAS  PubMed  Google Scholar 

  35. Maiese K (2016) Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders. Br J Clin Pharmacol 82(5):1245–1266

    Article  CAS  PubMed  Google Scholar 

  36. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. Jeon SM (2016) Regulation and function of AMPK in physiology and diseases. Exp Mol Med 48(7):e245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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

    Article  CAS  PubMed  Google Scholar 

  40. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

  1. Translational Medicine Research Center, Shanxi Medical University, Xinjiannanlu 56, Taiyuan, 030001, Shanxi, People’s Republic of China

    Huaping Zhang, Zhenxiang Zhao, Haixia Yu & Hui Zhou

  2. National Key Disciplines, Key Laboratory for Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, 030001, Shanxi, People’s Republic of China

    Xiaorong Yang & Xuefen Pang

Authors
  1. Huaping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaorong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xuefen Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhenxiang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haixia Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Huaping Zhang.

Ethics declarations

Conflict of interest

The authors declare that there are no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-018-3476-8

Keywords

Search

Navigation