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Resveratrol reduces intracellular reactive oxygen species levels by inducing autophagy through the AMPK-mTOR pathway

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Abstract

Oxidative stress induced by free fatty acid aggravates endothelial injury, which leads to diabetic cardiovascular complications. Reduction of intracellular oxidative stress may attenuate these pathogenic processes. The dietary polyphenol resveratrol reportedly exerts potential protective effects against endothelial injury. This study determined whether resveratrol can reduce the palmitic acid (PA)-induced generation of reactive oxygen species (ROS) and further explored the underlying molecular mechanisms. We found that resveratrol significantly reduced the PA-induced endothelial ROS levels in human aortic endothelial cells. Resveratrol also induced endothelial cell autophagy, which mediated the effect of resveratrol on ROS reduction. Resveratrol stimulated autophagy via the AMP-activated protein kinase (AMPK)-mTOR pathway. Taken together, these data suggest that resveratrol prevents PA-induced intracellular ROS by autophagy regulation via the AMPK-mTOR pathway. Thus, the induction of autophagy by resveratrol may provide a novel therapeutic candidate for cardioprotection in metabolic syndrome.

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References

  1. Incalza MA, D'Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol 2018; 100: 1–19

    Article  CAS  PubMed  Google Scholar 

  2. Morales CR, Pedrozo Z, Lavandero S, Hill JA. Oxidative stress and autophagy in cardiovascular homeostasis. Antioxid Redox Signal 2014; 20(3): 507–518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Saad MI, Abdelkhalek TM, Saleh MM, Kamel MA, Youssef M, Tawfik SH, Dominguez H. Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells. Endocrine 2015; 50(3): 537–567

    Article  CAS  PubMed  Google Scholar 

  4. Carrizzo A, Forte M, Damato A, Trimarco V, Salzano F, Bartolo M, Maciag A, Puca AA, Vecchione C. Antioxidant effects of resveratrol in cardiovascular, cerebral and metabolic diseases. Food Chem Toxicol 2013; 61: 215–226

    Article  CAS  PubMed  Google Scholar 

  5. Bonnefont-Rousselot D. Resveratrol and cardiovascular diseases. Nutrients 2016; 8(5): E250

    Article  CAS  PubMed  Google Scholar 

  6. Baxter RA. Anti-aging properties of resveratrol: review and report of a potent new antioxidant skin care formulation. J Cosmet Dermatol 2008; 7(1): 2–7

    Article  PubMed  Google Scholar 

  7. Xu M, Xue W, Ma Z, Bai J,Wu S. Resveratrol reduces the incidence of portal vein system thrombosis after splenectomy in a rat fibrosis model. Oxid Med Cell Longev 2016; 2016:7453849

    PubMed  PubMed Central  Google Scholar 

  8. Han SY, Choi YJ, Kang MK, Park JH, Kang YH. Resveratrol suppresses cytokine production linked to FceRI-MAPK activation in IgE-antigen complex-exposed basophilic mast cells and mice. Am J Chin Med 2015; 43(8): 1605–1623

    Article  CAS  PubMed  Google Scholar 

  9. Diaz-Gerevini GT, Repossi G, Dain A, Tarres MC, Das UN, Eynard AR. Beneficial action of resveratrol: how and why? Nutrition 2016; 32(2): 174–178

    Article  CAS  PubMed  Google Scholar 

  10. Novelle MG, Wahl D, Diéguez C, Bernier M, de Cabo R. Resveratrol supplementation: where are we now and where should we go? Ageing Res Rev 2015; 21: 1–15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Antonioli M, Di Rienzo M, Piacentini M, Fimia GM. Emerging mechanisms in initiating and terminating autophagy. Trends Biochem Sci 2017; 42(1): 28–41

    Article  CAS  PubMed  Google Scholar 

  12. Kiffin R, Bandyopadhyay U, Cuervo AM. Oxidative stress and autophagy. Antioxid Redox Signal 2006; 8(1-2): 152–162

    Article  CAS  PubMed  Google Scholar 

  13. Gu J, Hu W, Song ZP, Chen YG, Zhang DD, Wang CQ. Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity. Int Immunopharmacol 2016; 32: 1–7

    Article  CAS  PubMed  Google Scholar 

  14. Nagata D, Mogi M, Walsh K. AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress. J Biol Chem 2003; 278(33): 31000–31006

    Article  CAS  PubMed  Google Scholar 

  15. He C, Li H, Viollet B, Zou MH, Xie Z. AMPK suppresses vascular inflammation in vivo by inhibiting signal transducer and activator of transcription-1. Diabetes 2015; 64(12): 4285–4297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Youn JY, Wang T, Cai H. An ezrin/calpain/PI3K/AMPK/eNOSs1179 signaling cascade mediating VEGF-dependent endothelial nitric oxide production. Circ Res 2009; 104(1): 50–59

    Article  CAS  PubMed  Google Scholar 

  17. Zou MH, Hou XY, Shi CM, Nagata D, Walsh K, Cohen RA. Modulation by peroxynitrite of Akt-and AMP-activated kinasedependent Ser1179 phosphorylation of endothelial nitric oxide synthase. J Biol Chem 2002; 277(36): 32552–32557

    Article  CAS  PubMed  Google Scholar 

  18. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008; 30(2): 214–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang L, Wei J, Ren L, Zhang J, Wang J, Jing L, Yang M, Yu Y, Sun Z, Zhou X. Endosulfan induces autophagy and endothelial dysfunction via the AMPK/mTOR signaling pathway triggered by oxidative stress. Environ Pollut 2017; 220(Pt B): 843–852

    Article  CAS  PubMed  Google Scholar 

  20. Jo HK, Kim GW, Jeong KJ, Kim DY, Chung SH. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway. Biol Pharm Bull 2014; 37(8): 1341–1351

    Article  CAS  PubMed  Google Scholar 

  21. Li XN, Song J, Zhang L, LeMaire SA, Hou X, Zhang C, Coselli JS, Chen L, Wang XL, Zhang Y, Shen YH. Activation of the AMPKFOXO3 pathway reduces fatty acid-induced increase in intracellular reactive oxygen species by upregulating thioredoxin. Diabetes 2009; 58(10): 2246–2257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Koshkin V, Wang X, Scherer PE, Chan CB, Wheeler MB. Mitochondrial functional state in clonal pancreatic β-cells exposed to free fatty acids. J Biol Chem 2003; 278(22): 19709–19715

    Article  CAS  PubMed  Google Scholar 

  23. Lee Y, Lee HY, Gustafsson AB. Regulation of autophagy by metabolic and stress signaling pathways in the heart. J Cardiovasc Pharmacol 2012; 60(2): 118–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Elnakish MT, Hassanain HH, Janssen PM, Angelos MG, Khan M. Emerging role of oxidative stress in metabolic syndrome and cardiovascular diseases: important role of Rac/NADPH oxidase. J Pathol 2013; 231(3): 290–300

    Article  CAS  PubMed  Google Scholar 

  25. Hutcheson R, Rocic P. The metabolic syndrome, oxidative stress, environment, and cardiovascular disease: the great exploration. Exp Diabetes Res 2012; 2012: 271028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 2004; 22(3): 169–188

    Article  CAS  PubMed  Google Scholar 

  27. Hao HD, He LR. Mechanisms of cardiovascular protection by resveratrol. J Med Food 2004; 7(3): 290–298

    Article  CAS  PubMed  Google Scholar 

  28. Xia N, Förstermann U, Li H. Resveratrol and endothelial nitric oxide. Molecules 2014; 19(10): 16102–16121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016; 12(1): 1–222

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gu J, Hu W, Song ZP, Chen YG, Zhang DD, Wang CQ. Resveratrol-induced autophagy promotes survival and attenuates doxorubicin-induced cardiotoxicity. Int Immunopharmacol 2016; 32: 1–7

    Article  CAS  PubMed  Google Scholar 

  31. Wu SB, Wu YT, Wu TP, Wei YH. Role of AMPK-mediated adaptive responses in human cells with mitochondrial dysfunction to oxidative stress. Biochim Biophys Acta 2014; 1840(4): 1331–1344

    Article  CAS  PubMed  Google Scholar 

  32. Fan X, Wang J, Hou J, Lin C, Bensoussan A, Chang D, Liu J, Wang B. Berberine alleviates ox-LDL induced inflammatory factors by upregulation of autophagy via AMPK/mTOR signaling pathway. J Transl Med 2015; 13:92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zheng XT, Wu ZH, Wei Y, Dai JJ, Yu GF, Yuan F, Ye LC. Induction of autophagy by salidroside through the AMPK-mTOR pathway protects vascular endothelial cells from oxidative stress-induced apoptosis. Mol Cell Biochem 2017; 425(1-2): 125–138

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The present work was funded by outstanding young scientist research grant in Shandong Province (No. 2013BSE27128), National Natural Science Foundation of China (No. 81370943), China Postdoctoral Science Foundation (No. 2015M580334) and Shanghai Municipal Health and Family Planning Commission Project (No. 20134189).

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Authors and Affiliations

  1. Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, 200233, China

    Jun Song, Yeping Huang, Jing Yan, Cheng Hu & Weiping Jia

  2. Department of Endocrinology, Qilu Hospital of Shandong University, Jinan, 250012, China

    Jun Song, Ruxing Zhao & Li Chen

  3. Department of Endocrinology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China

    Jun Song

  4. Department of Geriatrics, Qingdao Haici Medical Treatment Group, Qingdao, 266000, China

    Wenjian Zheng

  5. Huangdao Disease Prevention and Control Center, Qingdao, 266555, China

    Min Cheng

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  1. Jun Song
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  2. Yeping Huang
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  3. Wenjian Zheng
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  4. Jing Yan
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  5. Min Cheng
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  7. Li Chen
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  8. Cheng Hu
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  9. Weiping Jia
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Correspondence to Cheng Hu or Weiping Jia.

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Song, J., Huang, Y., Zheng, W. et al. Resveratrol reduces intracellular reactive oxygen species levels by inducing autophagy through the AMPK-mTOR pathway. Front. Med. 12, 697–706 (2018). https://doi.org/10.1007/s11684-018-0655-7

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  • DOI: https://doi.org/10.1007/s11684-018-0655-7

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