Epigallocatechin-3-gallate pretreatment alleviates doxorubicin-induced ferroptosis and cardiotoxicity by upregulating AMPKα2 and activating adaptive autophagy
Huan He,
Liang Wang,
Yang Qiao,
Bin Yang,
Dong Yin,
Ming He
Affiliations
Huan He
Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China; Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang, 330006, China
Liang Wang
Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
Yang Qiao
Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang, 330006, China
Bin Yang
Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang, 330006, China
Dong Yin
Jiangxi Provincial Key Laboratory of Molecular Medicine, The Second Affiliated Hospital, Nanchang University, Nanchang, 330006, China; Corresponding author. No. 1, Minde Road, 330006, Nanchang, China.
Ming He
Institute of Cardiovascular Diseases, Jiangxi Academy of Clinical Medical Sciences, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China; Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang, 330006, China; Corresponding author. No. 461, Bayi Road, 330006, Nanchang, China.
Reports indicate that the mechanism of doxorubicin (Dox)-induced cardiotoxicity is very complex, involving multiple regulatory cell death forms. Furthermore, the clinical intervention effect is not ideal. Iron dependence, abnormal lipid metabolism, and excess reactive oxygen species generation, three characteristics of ferroptosis, are potential therapeutic intervention targets. Here, we confirmed in vitro and in vivo that at least autophagy, apoptosis, and ferroptosis are involved in Dox cardiotoxicity-induced damage. When the neonatal rat cardiomyocytes and H9C2 cells or C57BL/6 mice were subjected to Dox-induced cardiotoxicity, epigallocatechin-3-gallate pretreatment could effectively decrease iron accumulation, inhibit oxidative stress and abnormal lipid metabolism, and thereby alleviate Dox cardiotoxicity-induced ferroptosis and protect the myocardium according to multiple functional, enzymatic, and morphological indices. The underlying mechanism was verified to involve the upregulation and activation of AMP-activated protein kinase α2, which promoted adaptive autophagy, increased energy supply, and maintained mitochondrial function. We believe that epigallocatechin-3-gallate is a candidate phytochemical against Dox-induced cardiotoxicity.
