He Huan, Wang Liang, Qiao Yang, Yang Bin, Yin Dong, He Ming
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.
Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Redox Biol. 2021 Nov 11;48:102185. doi: 10.1016/j.redox.2021.102185.
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.
报告表明，阿霉素（Dox）诱导的心脏毒性机制非常复杂，涉及多种调节性细胞死亡形式。此外，临床干预效果并不理想。铁依赖性、脂质代谢异常和活性氧生成过多是铁死亡的三个特征，是潜在的治疗干预靶点。在此，我们在体外和体内证实，至少自噬、凋亡和铁死亡参与了Dox诱导的心脏毒性损伤。当新生大鼠心肌细胞和H9C2细胞或C57BL/6小鼠受到Dox诱导的心脏毒性时，表没食子儿茶素没食子酸酯预处理可有效减少铁积累，抑制氧化应激和脂质代谢异常，从而根据多种功能、酶学和形态学指标减轻Dox诱导的心脏毒性铁死亡并保护心肌。其潜在机制经证实涉及AMP活化蛋白激酶α2的上调和激活，这促进了适应性自噬，增加了能量供应并维持了线粒体功能。我们认为表没食子儿茶素没食子酸酯是一种抗Dox诱导心脏毒性的候选植物化学物质。
