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

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.

• Authors: Wei-Yin Wu, Yu-Kai Cui, Yi-Xiang Hong, Yun-Da Li, Yao Wu, Gang Li, Gui-Rong Li, Yan Wang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 20 Pg. 12141-12153 (10 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 32918384 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

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

Topics

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