Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Department of Cardiology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Mol Cell Cardiol. 2018 May;118:133-146. doi: 10.1016/j.yjmcc.2018.03.018. Epub 2018 Mar 31.
Myocardial infarction (MI), characterized by interruption of blood and oxygen to myocardium, is a common yet fatal cardiovascular event that causes progressive damage to myocardial tissue and eventually leads to heart failure. Previous studies have shown increased expression of microRNA-223 (miR-223) in infarcted myocardial tissues of humans and in rat models of MI. However, the role of miR-223 in cell survival during MI has not been elucidated. Thus, we aimed to investigate whether miR-223 participates in the regulation of cardiac ischemia-induced injury and to elucidate the underlying mechanisms of this process. qRT-PCR revealed that miR-223 expression levels are significantly upregulated in the myocardial tissues of rats with post-MI heart failure and in hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and H9c2 cells, which indicates that miR-223 may be associated with chronic ischemia. We also transfected NRCMs and H9c2 cells with miR-223 mimics or inhibitors in vitro, and the results revealed that increasing miR-223 expression protected cells from hypoxia-induced apoptosis and excessive autophagy, whereas decreasing miR-223 expression had contrasting effects. Further exploration of the mechanism showed that poly(ADP-ribose) polymerase 1 (PARP-1) is a target gene of miR-223 and that silencing PARP-1 prevented hypoxia-induced cell injury; additionally, silencing PARP-1 blocked the aggravated impact of miR-223 inhibitors. Thus, PARP-1 mediates the protective effects of miR-223 in hypoxia-treated cardiomyocytes. We also investigated the involvement of the Akt/mTOR pathway in the above phenomena. We found that miR-223 overexpression and PARP-1 silencing positively regulated the Akt/mTOR pathway and that treating cells with NVP-BEZ235 (BEZ235), a novel dual Akt/mTOR inhibitor, could reverse the inhibitory effects of both the miR-223 mimics and PARP-1 siRNA on hypoxia-induced apoptosis and autophagy. Taken together, our findings showed that miR-223 protects NRCMs and H9c2 cells from hypoxia-induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1; thus, miR-223 may be a potential target in the treatment of MI in the future.
心肌梗死（MI）的特征是心肌血液和氧气中断，是一种常见但致命的心血管事件，会导致心肌组织进行性损伤，最终导致心力衰竭。先前的研究表明，miR-223 在人类梗死心肌组织和 MI 大鼠模型中的表达增加。然而，miR-223 在 MI 期间细胞存活中的作用尚未阐明。因此，我们旨在研究 miR-223 是否参与调节心脏缺血诱导的损伤，并阐明这一过程的潜在机制。qRT-PCR 显示，心肌梗死后心力衰竭大鼠心肌组织和缺氧处理的新生大鼠心肌细胞（NRCMs）和 H9c2 细胞中 miR-223 的表达水平显著上调，这表明 miR-223 可能与慢性缺血有关。我们还在体外转染 miR-223 模拟物或抑制剂 NRCMs 和 H9c2 细胞，结果表明，增加 miR-223 表达可保护细胞免受缺氧诱导的凋亡和过度自噬，而降低 miR-223 表达则有相反的作用。进一步的机制探索表明，聚（ADP-核糖）聚合酶 1（PARP-1）是 miR-223 的靶基因，沉默 PARP-1 可阻止缺氧诱导的细胞损伤；此外，沉默 PARP-1 可阻断 miR-223 抑制剂的加重影响。因此，PARP-1 介导了 miR-223 在缺氧处理的心肌细胞中的保护作用。我们还研究了 Akt/mTOR 通路在上述现象中的参与情况。我们发现，miR-223 过表达和 PARP-1 沉默正向调节 Akt/mTOR 通路，并且用新型双重 Akt/mTOR 抑制剂 NVP-BEZ235（BEZ235）处理细胞可逆转 miR-223 模拟物和 PARP-1 siRNA 对缺氧诱导的凋亡和自噬的抑制作用。总之，我们的研究结果表明，miR-223 通过靶向 PARP-1 保护 NRCMs 和 H9c2 细胞免受缺氧诱导的凋亡和过度自噬，通过 Akt/mTOR 通路；因此，miR-223 可能是未来 MI 治疗的潜在靶点。
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