Suppression of Bim by microRNA-19a may protect cardiomyocytes against hypoxia-induced cell death via autophagy activation
Suppression of Bim by microRNA-19a may protect cardiomyocytes against hypoxia-induced cell death via autophagy activation
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microRNA-19a 抑制 Bim 可能通过自噬激活保护心肌细胞免受缺氧诱导的细胞死亡
DOI：
10.1016/j.toxlet.2016.05.019
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发表时间：
2016-08-22
影响因子：
3.5
通讯作者：
Ge, Jun-bo
中科院分区：
文献类型：
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作者：
Gao, Yan-hua;Qian, Ju-ying;Ge, Jun-bo
微血管阻塞（MO）是经皮冠状动脉介入治疗（PCI）的不良并发症之一，是导致再灌注治疗效果丧失的主要原因。利用实时定量聚合酶链反应（PCR）检测miR-17-92簇成员microRNA-19a，发现microRNA-19a在MO心肌中明显下调。尽管如此，miR-19a在MO中的作用及其潜在机制仍有待阐明。为此，采用体外心肌细胞微栓塞模型。我们的数据显示，缺氧暴露以一种时间依赖性的方式促进心肌细胞凋亡，并伴有miR-19a的降低。miR-19a过表达明显改善了缺氧诱导的细胞死亡（坏死和凋亡），至少部分是通过开启自噬来实现的。进一步的双荧光素酶报告试验和免疫印迹研究表明，mir -19a诱导的细胞保护可能部分通过调节细胞死亡的特异性靶Bcl-2相互作用介质Bim（一种凋亡激活剂）来实现。缺氧条件下，Bim充分干扰mir -19a诱导的LC3转化，增加心肌细胞凋亡。此外，用3-甲基腺嘌呤预处理的心肌细胞可以抵抗miR-19a的细胞保护作用，并显示出TUNEL染色和caspase-3活性显著增加。总之，miR-19a至少在一定程度上通过抑制Bim和随后的自噬激活来保护心肌细胞免受缺氧诱导的死亡。2016爱思唯尔爱尔兰有限公司版权所有。
Microvascular obstruction (MO), one of unfavorable complications of percutaneous coronary intervention (PCI), is responsible for the lost benefit of reperfusion therapy. Determination of microRNA-19a, a member of the miR-17-92 cluster, using quantitative real-time polymerase chain reaction (PCR) revealed notably down-regulated microRNA-19a, in myocardium with MO. Nonetheless, the role of miR-19a in MO and the underlying mechanism remains to be elucidated. To this end, an in vitro microembolization model in cardiomyocytes was used. Our data revealed that hypoxic exposure prompted cardiomyocyte apoptosis in a time-dependent manner accompanied by reduced miR-19a. miR-19a overexpression clearly ameliorated hypoxia-induced cell death (necrosis and apoptosis), at least in part, through switching on autophagy. Further dual-luciferase reporter assay and immunoblotting studies demonstrated that miR-19a-induced cytoprotection might be achieved in part through modulation of the specific target Bcl-2 interacting mediator of cell death, Bim, an apoptotic activator. Bim sufficiently interfered with miR-19a-induced LC3 conversion and increased cardiomyocyte apoptosis under hypoxia. Moreover, cardiomyocytes pretreated with 3-methyladenine conferred resistance to the cytoprotective effect of miR-19a and displayed notably increased TUNEL staining and caspase-3 activity. In conclusion, miR-19a protected cardiomyocytes against hypoxia-induced lethality at least in part via Bim suppression and subsequently autophagy activation. (C) 2016 Elsevier Ireland Ltd. All rights reserved.