Foxo3a inhibits mitochondrial fission and protects against doxorubicin-induced cardiotoxicity by suppressing MIEF2
Foxo3a inhibits mitochondrial fission and protects against doxorubicin-induced cardiotoxicity by suppressing MIEF2
复制标题
Foxo3a 通过抑制 MIEF2 抑制线粒体裂变并防止阿霉素诱导的心脏毒性
DOI：
10.1016/j.freeradbiomed.2017.01.037
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发表时间：
2017-03-01
影响因子：
7.4
通讯作者：
Wang, Kun
中科院分区：
文献类型：
--
作者：
Zhou, Luyu;Li, Ruibei;Wang, Kun
阿霉素（DOX）作为一种化疗药物被广泛用于治疗多种人类肿瘤。然而，限制其临床应用的主要因素是其心脏毒性。调节DOX诱导的心脏毒性的分子组分和详细机制在很大程度上仍未确定。在这里，我们报告了Foxo3a在心肌细胞和小鼠心脏中响应于DOX治疗而下调。Foxo3a减弱心肌细胞中DOX诱导的线粒体分裂和凋亡心脏特异性Foxo3a转基因小鼠在DOX施用后显示减少的线粒体分裂、细胞凋亡和心脏毒性。此外，Foxo3a直接靶向线粒体动力学蛋白49 kDa（MIEF2），并在转录水平上抑制其表达。在心肌细胞和体内，MIEF2的敲低减少了DOX诱导的线粒体分裂和凋亡。此外，MIEF2的敲低保护心脏免受DOX诱导的心脏毒性。我们的研究确定了一种由Foxo3a和MIEF2组成的介导DOX心脏毒性的新途径。这一发现为癌症治疗和心脏保护提供了一种有前途的治疗策略。
Doxorubicin (DOX) as a chemotherapeutic drug is widely used to treat a variety of human tumors. However, a major factor limiting its clinical use is its cardiotoxicity. The molecular components and detailed mechanisms regulating DOX-induced cardiotoxicity remain largely unidentified. Here we report that Foxo3a is down regulated in the cardiomyocyte and mouse heart in response to DOX treatment. Foxo3a attenuates DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. Cardiac specific Foxo3a transgenic mice show reduced mitochondrial fission, apoptosis and cardiotoxicity upon DOX administration. Furthermore, Foxo3a directly targets mitochondrial dynamics protein of 49 kDa (MIEF2) and suppresses its expression at transcriptional level. Knockdown of MIEF2 reduces DOX-induced mitochondrial fission and apoptosis in cardiomyocytes and in vivo. Also, knockdown of MIEF2 protects heart from DOX-induced cardiotoxicity. Our study identifies a novel pathway composed of Foxo3a and MIEF2 that mediates DOX cardiotoxicity. This discovery provides a promising therapeutic strategy for the treatment of cancer therapy and cardioprotection.