MicroRNA-124 regulates cardiomyocyte apoptosis and myocardial infarction through targeting Dhcr24
MicroRNA-124 regulates cardiomyocyte apoptosis and myocardial infarction through targeting Dhcr24
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MicroRNA-124通过靶向Dhcr24调节心肌细胞凋亡和心肌梗死
DOI：
10.1016/j.yjmcc.2019.05.007
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发表时间：
2019-07-01
影响因子：
5
通讯作者：
Zhang, Li
中科院分区：
文献类型：
--
作者：
Han, Fei;Chen, Qishan;Zhang, Li
目的：最近有报道称 microRNA-124（miR-124）在心血管疾病中升高。本研究旨在探讨miR-124在心肌细胞和心肌梗死中的确切作用，明确其功能靶点及其调控机制。 方法与结果：采用培养心肌细胞、心肌梗死小鼠模型和临床数据研究miR-124对心肌缺血的影响。 miR-124 的表达在 H2O2 和缺氧诱导的心肌细胞损伤中上调。 miR-124 过表达显着增加心肌细胞凋亡，而 miR-124 抑制则减弱细胞死亡。 3β-羟基类固醇-Delta24 还原酶 (Dhcr24) 是一种参与胆固醇合成和多种疾病的多功能酶，被确定为心肌细胞中 miR-124 的新功能靶点。 miR-124-Dhcr24 轴负责心肌细胞凋亡调节。此外，心肌梗塞在体内诱导 miR-124 激活和 Dhcr24 减少。通过心肌内注射 agomiR 或 antagomiR 调节 miR-124 能够控制小鼠心肌细胞凋亡和心肌梗死。更重要的是，在急性心肌梗死（AMI）患者中，循环miR-124也被观察到升高，并且与心肌损伤和心脏功能相关。结论：我们的研究结果有力地证明，靶向Dhcr24的miR-124可调节氧化应激和缺氧诱导的心肌细胞凋亡和心肌梗死。 miR-124-Dhcr24 轴可能是 AMI 的潜在生物标志物和治疗靶点。
Aims: microRNA-124(miR-124) has recently been reported to be elevated in cardiovascular disease. In this study, we aimed to investigate the exact role of miR-124 in cardiomyocytes and myocardial infarction, identifying the functional target and its regulatory mechanisms.Methods and results: Cultured cardiomyocytes, myocardial-infarction mouse model, and clinical data were used to study the effects of miR-124 on myocardial ischemia. Expression of miR-124 was up-regulated in H2O2 and hypoxia induced cardiomyocyte injury. miR-124 over-expression significantly increased cardiomyocyte apoptosis, whereas miR-124 inhibition attenuated cell death. 3 beta-hydroxysteroid-Delta24 reductase (Dhcr24), a multi-functional enzyme implicated in cholesterol synthesis and various diseases, was identified as a novel functional target of miR-124 in cardiac myocytes. The miR-124-Dhcr24 axis was responsible for cardiomyocyte apoptosis regulation. Furthermore, myocardial infarction induced miR-124 activation and Dhcr24 reduction in vivo. Modulation of miR-124 by intra-myocardial injection of agomiR or antagomiR was capable of manipulating cardiomyocyte apoptosis and myocardial infarction in mice. More importantly, circulating miR-124 was also observed to be elevated in acute myocardial infarction (AMI) patients and was correlated with myocardial injury and cardiac function.Conclusion: Our findings strongly demonstrated that miR-124 targeting Dhcr24 regulates oxidative stress and hypoxia induced cardiomyocyte apoptosis and myocardial infarction. The miR-124-Dhcr24 axis could be a potential biomarker as well as the therapeutic target for AMI.