AMPK/PGC1α activation by melatonin attenuates acute doxorubicin cardiotoxicity via alleviating mitochondrial oxidative damage and apoptosis

Dong Liu, Zhiqiang Ma, Shouyin Di, Yang Yang, Jingang Yang, Liqun Xu, Russel J Reiter, Shubin Qiao, Jiansong Yuan

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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 1 μM DOX and C57BL/6 mice treated with DOX (20 mg/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 activation may represent a new mechanism for melatonin exerted protection against acute DOX cardiotoxicity through preservation of mitochondrial homeostasis and alleviation of oxidative stress and apoptosis.

Original languageEnglish (US)
Pages (from-to)59-72
Number of pages14
JournalFree Radical Biology and Medicine
Volume129
DOIs
StatePublished - Dec 1 2018

Keywords

  • AMPK
  • Apoptosis
  • Cardiotoxicity
  • Doxorubicin
  • Melatonin
  • Mitochondria
  • PGC1α

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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