AMPK/PGC1 α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis.

AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis.
Free Radic Biol Med. 2018 Aug 30;:
Authors: Liu D, Ma Z, Di S, Yang Y, Yang J, Xu L, Reiter RJ, Qiao S, Yuan J
Abstract
Doxorubicin (DOX) is a highly effective anticancer anthracycline drug, but its side effects at the level of the heart has limited its widespread clinical application. Melatonin is a documented potent antioxidant, nontoxic and cardioprotective agent, and it is involved in maintaining mitochondrial homeostasis and function. The present study established acute DOX-induced cardiotoxicity models in both H9c2 cells incubated with 1μM DOX and C57BL/6 mice treated with DOX (20mg/kg cumulative dose). Melatonin markedly alleviated the DOX-induced acute cardiac dysfunction and myocardial injury. Both in vivo and in vitro studies verified that melatonin inhibited DOX-induced mitochondrial dysfunction and morphological disorders, apoptosis, and oxidative stress via the activation of AMPK and upregulation of PGC1α with its downstream signaling (NRF1, TFAM and UCP2). These effects were reversed by the use of AMPK siRNA or PGC1α siRNA in H9c2 cells, and were also negated by the cotreatment with AMPK inhibitor Compound C in vivo. Moreover, PGC1α knockdown was without effect on the AMPK phosphorylation induced by melatonin in the DOX treated H9c2 cells. Therefore, AMPK/PGC1α pathway activa...

Source: Free Radical Biology and Medicine - August 30, 2018 Category: Biology Authors: Liu D, Ma Z, Di S, Yang Y, Yang J, Xu L, Reiter RJ, Qiao S, Yuan J Tags: Free Radic Biol Med Source Type: research