Cardioprotection by resveratrol: A novel mechanism via autophagy involving the mTORC2 pathway

Narasimman Gurusamy, Istvan Lekli, Subhendu Mukherjee, Diptarka Ray, Md Kaimul Ahsan, Mihaela Gherghiceanu, Lawrence M. Popescu, Dipak K. Das

Research output: Contribution to journalArticle

190 Citations (Scopus)

Abstract

Aims: On the basis of our previous reports that cardioprotection induced by ischaemic preconditioning induces autophagy and that resveratrol, a polyphenolic antioxidant present in grapes and red wine induces preconditioning-like effects, we sought to determine if resveratrol could induce autophagy. Methods and results: Resveratrol at lower doses (0.1 and 1 μM in H9c2 cardiac myoblast cells and 2.5 mg/kg/day in rats) induced cardiac autophagy shown by enhanced formation of autophagosomes and its component LC3-II after hypoxia-reoxygenation or ischaemia-reperfusion. The autophagy was attenuated with the higher dose of resveratrol. The induction of autophagy was correlated with enhanced cell survival and decreased apoptosis. Treatment with rapamycin (100 nM), a known inducer of autophagy, did not further increase autophagy compared with resveratrol alone. Autophagic inhibitors, wortmannin (2 μM) and 3-methyladenine (10 mM), significantly attenuated the resveratrol-induced autophagy and induced cell death. The activation of mammalian target of rapamycin (mTOR) was differentially regulated by low-dose resveratrol, i.e. the phosphorylation of mTOR at serine 2448 was inhibited, whereas the phosphorylation of mTOR at serine 2481 was increased, which was attenuated with a higher dose of resveratrol. Although resveratrol attenuated the activation of mTOR complex 1, low-dose resveratrol significantly induced the expression of Rictor, a component of mTOR complex 2, and activated its downstream survival kinase Akt (Ser 473). Resveratrol-induced Rictor was found to bind with mTOR. Furthermore, treatment with Rictor siRNA attenuated the resveratrol-induced autophagy. Conclusion: Our results indicate that at lower dose, resveratrol-mediated cell survival is, in part, mediated through the induction of autophagy involving the mTOR-Rictor survival pathway.

Original languageEnglish
Pages (from-to)103-112
Number of pages10
JournalCardiovascular research
Volume86
Issue number1
DOIs
Publication statusPublished - Apr 2010

Keywords

  • Autophagy
  • Cardioprotection
  • Cell survival
  • Resveratrol
  • Rictor
  • mTOR

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Gurusamy, N., Lekli, I., Mukherjee, S., Ray, D., Ahsan, M. K., Gherghiceanu, M., Popescu, L. M., & Das, D. K. (2010). Cardioprotection by resveratrol: A novel mechanism via autophagy involving the mTORC2 pathway. Cardiovascular research, 86(1), 103-112. https://doi.org/10.1093/cvr/cvp384