Doxorubicin cardiomyopathy is ameliorated by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules

J Cell Mol Med. 2020 Oct;24(20):12141-12153. doi: 10.1111/jcmm.15859. Epub 2020 Sep 11.

Abstract

Doxorubicin cardiotoxicity is frequently reported in patients undergoing chemotherapy. The present study investigates whether cardiomyopathy induced by doxorubicin can be improved by the natural flavone acacetin in a mouse model and uncovers the potential molecular mechanism using cultured rat cardiomyoblasts. It was found that the cardiac dysfunction and myocardial fibrosis induced by doxorubicin were significantly improved by acacetin in mice with impaired Nrf2/HO-1 and Sirt1/pAMPK molecules, which is reversed by acacetin treatment. Doxorubicin decreased cell viability and increased ROS production in rat cardiomyoblasts; these effects are significantly countered by acacetin (0.3-3 μM) in a concentration-dependent manner via activating Sirt1/pAMPK signals and enhancing antioxidation (Nrf2/HO-1 and SOD1/SOD2) and anti-apoptosis. These protective effects were abolished in cells with silencing Sirt1. The results demonstrate for the first time that doxorubicin cardiotoxicity is antagonized by acacetin via Sirt1-mediated activation of AMPK/Nrf2 signal molecules, indicating that acacetin may be a drug candidate used clinically for protecting against doxorubicin cardiomyopathy.

Keywords: Sirt1; acacetin; antioxidant; cardiotoxicity; doxorubicin; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Antioxidants / metabolism
  • Apoptosis / drug effects
  • Cardiomyopathies / chemically induced*
  • Cardiomyopathies / drug therapy*
  • Cardiomyopathies / metabolism
  • Cardiotonic Agents / pharmacology
  • Cardiotonic Agents / therapeutic use
  • Cell Line
  • Cell Survival / drug effects
  • Doxorubicin / adverse effects*
  • Flavones / pharmacology
  • Flavones / therapeutic use*
  • Gene Silencing
  • Heart Ventricles / drug effects
  • Heart Ventricles / pathology
  • Male
  • Mice, Inbred C57BL
  • Myocardium / pathology
  • NF-E2-Related Factor 2 / metabolism*
  • Rats
  • Reactive Oxygen Species / metabolism
  • Signal Transduction*
  • Sirtuin 1 / metabolism*

Substances

  • Antioxidants
  • Cardiotonic Agents
  • Flavones
  • NF-E2-Related Factor 2
  • Reactive Oxygen Species
  • Doxorubicin
  • AMP-Activated Protein Kinases
  • Sirtuin 1
  • acacetin