Fei Han1, Qishan Chen2, Jia Su1, Ancheng Zheng1, Kai Chen1, Shasha Sun1, Hong Wu1, Liujun Jiang1, Xiaolei Xu1, Mei Yang1, Feng Yang1, Jianhua Zhu3, Li Zhang4. 1. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. 2. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: qishan.chen@zju.edu.cn. 3. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: 1183039@zju.edu.cn. 4. Department of Cardiology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China. Electronic address: li_zhang@zju.edu.cn.
Abstract
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. 3β-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.
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-infarctionmouse 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. 3β-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.