SESN2 protects against doxorubicin-induced cardiomyopathy via rescuing mitophagy and improving mitochondrial function
SESN2 protects against doxorubicin-induced cardiomyopathy via rescuing mitophagy and improving mitochondrial function
复制标题
SESN2 通过拯救线粒体自噬和改善线粒体功能来预防阿霉素诱导的心肌病
DOI：
10.1016/j.yjmcc.2019.06.005
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发表时间：
2019-08-01
影响因子：
5
通讯作者：
Liu, Peiqing
中科院分区：
文献类型：
--
作者：
Wang, Panxia;Wang, Luping;Liu, Peiqing
阿霉素（Dox）在癌症治疗中的临床应用因其严重的心脏毒性而受到限制。我们之前的研究和其他研究已经认识到线粒体功能障碍是阿霉素引起的心脏毒性的共同特征。然而，线粒体疾病的潜在机制仍然很大程度上未知。 SESN2 是一种高度保守的应激诱导蛋白，参与心血管疾病中的线粒体功能和自噬。本研究旨在探讨SESN2是否影响Dox诱导的心脏毒性及其潜在机制。用 Dox 处理 Sprague-Dawley 大鼠和新生大鼠心肌细胞。评估SESN2表达。通过功能获得和丧失实验评估 SESN2 对 Dox 诱导的心脏毒性的影响。使用超声心动图参数、形态学和组织学分析、透射电子显微镜和免疫荧光测定来评估心脏和线粒体功能。 Dox 刺激后 SESN2 的蛋白表达显着降低。通过 sgRNA 和 Dox 治疗敲除 SESN2 都会导致 Parkin 介导的线粒体自噬受到抑制，显着心肌细胞凋亡和线粒体功能障碍。 SESN2 的异位表达可有效防止 Dox 诱导的心肌细胞凋亡、线粒体损伤和心功能障碍。从机制上讲，SESN2 与 Parkin 和 p62 相互作用，促进 Parkin 积累到线粒体，然后减轻 Dox 引起的 Parkin 介导的线粒体自噬抑制。最终，SESN2 过表达后受损线粒体的清除和线粒体功能得到改善。 SESN2 通过改善线粒体功能和线粒体自噬来防止 Dox 诱导的心脏毒性。这些结果确立了 SESN2 作为线粒体功能的关键参与者，并为 Dox 诱导的心肌病提供了潜在的治疗方法。
The clinical application of doxorubicin (Dox) in cancer therapy is limited by its serious cardiotoxicity. Our previous studies and others have recognized that mitochondrial dysfunction is the common feature of Dox-induced cardiotoxicity. However, mechanisms underlying mitochondrial disorders remained largely unknown. SESN2, a highly conserved and stress-inducible protein, is involved in mitochondrial function and autophagy in cardiovascular diseases. This study aimed to investigate whether SESN2 affects Dox-induced cardiotoxicity and the underlying mechanisms. Sprague-Dawley rats and neonatal rat cardiomyocytes were treated with Dox. SESN2 expression was assessed. The effects of SESN2 on Dox-induced cardiotoxicity were assessed by functional gain and loss experiments. Echocardiographie parameters, morphological and histological analyses, transmission electron microscope and immunofluorescence assays were used to assess cardiac and mitochondrial function. The protein expression of SESN2 was significantly reduced following Dox stimulation. Both knockout of SESN2 by sgRNA and Dox treatment resulted in the inhibition of Parkin-mediated mitophagy, marked cardiomyocytes apoptosis and mitochondria dysfunction. Ectopic expression of SESN2 effectively protected against Dox-induced cardiomyocyte apoptosis, mitochondrial injury and cardiac dysfunction. Mechanistically, SESN2 interacted with Parkin and p62, promoted accumulation of Parkin to mitochondria and then alleviated Dox-caused inhibition of Parkin mediated mitophagy. Ultimately, the clearance of damaged mitochondria and mitochondrial function were improved following SESN2 overexpression. SESN2 protected against Dox-induced cardiotoxicity through improving mitochondria function and mitophagy. These results established SESN2 as a key player in mitochondrial function and provided a potential therapeutic approach to Dox-induced cardiomyopathy.