He Ling, Wang Jihong, Yang Yuting, Zou Pengtao, Xia Zirong, Li Juxiang
Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Toxicology. 2022 Mar 15;469:153119. doi: 10.1016/j.tox.2022.153119. Epub 2022 Feb 5.
Doxorubicin (DOX) is a potent anthracycline chemotherapeutic drug. DOX-induced cardiotoxicity (DIC) limits its application in cancer treatment, as this complication is detrimental and fatal. Reactive oxygen species (ROS) production, autophagic dysfunction and cell death are crucial factors related to DIC. Previous studies have shown that SIRT4 is associated with cardiac energy metabolism, cardiac mitochondrial dysfunction and cardiac cell death, but it is unclear whether SIRT4 affects DOX-induced cardiac injury. Our data suggested that SIRT4 overexpression in vivo and in vitro could alleviate DIC by improving cardiac function and reducing cardiomyocyte apoptosis and autophagy. However, autophagy activation by rapamycin abolished the protective effect of SIRT4 overexpression on DIC. Furthermore, in the context of DOX treatment, SIRT4 overexpression activated the Akt/mTOR signaling pathway and inhibited autophagy through the Akt/mTOR signaling pathway. Our findings indicate that SIRT4 overexpression protects against DIC by inhibiting Akt/mTOR-dependent autophagy. These findings may provide a prospective therapeutic target for DIC.
多柔比星（DOX）是一种强效的蒽环类化疗药物。多柔比星诱导的心脏毒性（DIC）限制了其在癌症治疗中的应用，因为这种并发症具有危害性且可能致命。活性氧（ROS）生成、自噬功能障碍和细胞死亡是与DIC相关的关键因素。先前的研究表明，SIRT4与心脏能量代谢、心脏线粒体功能障碍和心脏细胞死亡有关，但尚不清楚SIRT4是否影响多柔比星诱导的心脏损伤。我们的数据表明，体内和体外的SIRT4过表达可通过改善心脏功能、减少心肌细胞凋亡和自噬来减轻DIC。然而，雷帕霉素激活自噬消除了SIRT4过表达对DIC的保护作用。此外，在多柔比星治疗的情况下，SIRT4过表达激活了Akt/mTOR信号通路，并通过Akt/mTOR信号通路抑制自噬。我们的研究结果表明，SIRT4过表达通过抑制Akt/mTOR依赖性自噬来预防DIC。这些发现可能为DIC提供一个潜在的治疗靶点。
