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

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 microM 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 microM) 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.

• Authors: Narasimman Gurusamy, Istvan Lekli, Subhendu Mukherjee, Diptarka Ray, Md Kaimul Ahsan, Mihaela Gherghiceanu, Lawrence M Popescu, Dipak K Das
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 86 Issue 1 Pg. 103-12 (Apr 01 2010) ISSN: 1755-3245 [Electronic] England
• PMID: 19959541 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cardiotonic Agents
• Carrier Proteins
• Crtc1 protein, rat
• Intracellular Signaling Peptides and Proteins
• Rapamycin-Insensitive Companion of mTOR Protein
• Stilbenes
• Transcription Factors
• rictor protein, rat
• mTOR protein, rat
• Protein Serine-Threonine Kinases
• TOR Serine-Threonine Kinases
• Resveratrol

Topics

• Animals
• Apoptosis (drug effects)
• Autophagy (drug effects, physiology)
• Cardiotonic Agents (pharmacology)
• Carrier Proteins (metabolism)
• Cell Line
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Myoblasts, Cardiac (cytology, drug effects, metabolism)
• Myocardium (cytology)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (metabolism)
• Rapamycin-Insensitive Companion of mTOR Protein
• Rats
• Rats, Sprague-Dawley
• Resveratrol
• Stilbenes (pharmacology)
• TOR Serine-Threonine Kinases
• Transcription Factors (metabolism)