MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.
MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.
复制标题
在阿霉素心脏毒性中，MicroRNA-532-3p 通过靶向具有 caspase 募集结构域的凋亡阻遏蛋白来调节线粒体裂变
DOI：
10.1038/cddis.2015.41
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发表时间：
2015-03-12
影响因子：
9
通讯作者：
Li PF
中科院分区：
文献类型：
--
作者：
Wang JX;Zhang XJ;Feng C;Sun T;Wang K;Wang Y;Zhou LY;Li PF
多柔比星（DOX）是一种广谱抗肿瘤药物，但其心脏毒性限制了其临床应用。然而，DOX诱导的心肌病的潜在机制仍不清楚。在此，我们观察到在DOX处理后，小鼠心脏和心肌细胞中具有半胱天冬酶募集结构域（ARC）的凋亡抑制因子下调。此外，ARC的增强表达减弱了DOX诱导的心肌细胞线粒体分裂和凋亡。ARC转基因小鼠在DOX施用后表现出降低的心脏毒性。DOX诱导的线粒体分裂需要动力蛋白相关蛋白1（Drp 1）的活性。在阐明DOX处理后ARC下调的分子机制时，发现miR-532- 3 p直接靶向ARC并参与DOX诱导的线粒体分裂和凋亡。miR-532- 3 p不参与DOX诱导的癌细胞凋亡。总之，这些发现提供了新的证据，证明miR-532- 3 p和ARC构成了调节DOX心脏毒性的抗凋亡途径。因此，基于ARC和miR-532- 3 p的新治疗策略的开发对于克服癌症治疗的化学疗法的心脏毒性是有希望的。
Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.
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影响因子：
37.8
作者：
Lebrecht, D;Setzer, B;Walker, UA
通讯作者：
Walker, UA
影响因子：
10.8
作者：
Horie T;Ono K;Nishi H;Nagao K;Kinoshita M;Watanabe S;Kuwabara Y;Nakashima Y;Takanabe-Mori R;Nishi E;Hasegawa K;Kita T;Kimura T
通讯作者：
Kimura T
影响因子：
11.8
作者：
Cassidy-Stone, Ann;Chipuk, Jerry E.;Nunnari, Jodi
通讯作者：
Nunnari, Jodi
影响因子：
4.8
作者：
James, DI;Parone, PA;Martinou, JC
通讯作者：
Martinou, JC
影响因子：
64.5
作者：
Montessuit S;Somasekharan SP;Terrones O;Lucken-Ardjomande S;Herzig S;Schwarzenbacher R;Manstein DJ;Bossy-Wetzel E;Basañez G;Meda P;Martinou JC
通讯作者：
Martinou JC