Resveratrol suppresses doxorubicin-induced cardiotoxicity by disrupting E2F1 mediated autophagy inhibition and apoptosis promotion

Abstract

The clinical use of doxorubicin (DOX) is limited by cardiotoxicity, involving the dysregulation of autophagy and apoptosis in the myocardium, which were partly reversed by resveratrol (RSV) supplement. However, a definitive mechanisms accounting for DOX's cardiotoxicity and the protective role of RSV remain poorly defined. The aim of the present study was to clarify the specific role of E2F transcription factor 1 (E2F1) in regulating autophagy and apoptosis in DOX-induced cardiotoxicity as well as the protective effects of RSV. Autophagy and apoptosis were successfully induced by the serum deprivation strategy in H9c2 cardiomyocytes. DOX inhibited autophagy through activating E2F1/mammalian target of rapamycin complex 1 (mTORC1) pathway and further induced apoptosis by activating E2F1/AMP-activated protein kinase α2 (AMPKα2) pathway in starved H9C2 cells. And RSV supplement showed increased autophagy and decreased apoptosis, accompanied with inhibitory effect on E2F1/mTORC1 as well as E2F1/AMPKα2 pathway. Moreover, the favorable effect of RSV on autophagy and apoptosis was dependent on E2F1. The same result was observed in the mouse model of DOX-induced cardiotoxicity in both non-myocardial ischemia and myocardial ischemia condition. Injection with DOX and RSV in combination, resulted in a reduced apoptotic ratio and activated autophagy process compared with the DOX treatment alone. In conclusions, RSV, which has been suggested to attenuate DOX-induced cytotoxicity, significantly blocks induction of E2F1/mTORC1 and E2F1/AMPKα2 pathway by DOX, leading to acceleratory autophagy and inhibitory apoptosis. And E2F1 plays a key role for the protective effect of RSV.

Keywords: Apoptosis; Autophagy; Cardiotoxicity; Doxorubicin; E2F1; Resveratrol.