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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.