MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction.
MicroRNA-210 Controls Mitochondrial Metabolism and Protects Heart Function in Myocardial Infarction.
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DOI：
10.1161/circulationaha.121.056929
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发表时间：
2022-04-12
期刊：
影响因子：
37.8
通讯作者：
Zhang, Lubo
中科院分区：
文献类型：
--
作者：
Song, Rui;Dasgupta, Chiranjib;Mulder, Cassidy;Zhang, Lubo
缺血性心脏病仍然是全球主要的死亡原因。在这项研究中，我们验证了microRNA-210通过控制线粒体生物能量学和活性氧(ROS)通量来保护心脏免受心肌缺血-再灌注(IR)损伤的假设。通过比较microRNA-210缺陷小鼠和野生型小鼠的功能丧失和功能获得实验，研究了急性IR状态下的心肌梗死。超声心动图评价心功能。心肌线粒体生物能量学检测采用海马XF24型分析仪。在雄性小鼠的心肌缺血再灌注后6周内，microRNA-210缺乏显著地加重了心功能不全，而雌性小鼠则没有。静脉注射microRNA-210可阻断上述作用，恢复心肌IR损伤和心功能不全。线粒体代谢分析显示，在IR损伤过程中，microRNA-210抑制了心肌线粒体的氧耗，增加了糖酵解活性，降低了线粒体的ROS流量。一致地，用MitoQ抑制线粒体ROS可以逆转microRNA-210缺乏的效果。从机制上讲，我们发现线粒体甘油-3-磷酸脱氢酶(GPD2)是心脏中microRNA-210的一个新靶点，功能丧失和功能获得实验表明，GPD2在microRNA-210介导的线粒体代谢和ROS通量的影响中发挥了关键作用。抑制GPD2基因的表达可逆转由microRNA-210缺乏引起的线粒体ROS生成增加和心肌梗死，并改善IR治疗后的左室短轴缩短率和射血分数。靶向GPD2的microRNA-210控制线粒体生物能和ROS通量，并在IR损伤的情况下改善心肌梗死小鼠的心功能。这一发现为治疗缺血性心脏病的机制和治疗目标提供了新的见解。
Ischemic heart disease remains a leading cause of death worldwide. In this study, we test the hypothesis that microRNA-210 protects the heart from myocardial ischemia-reperfusion (IR) injury by controlling mitochondrial bioenergetics and reactive oxygen species (ROS) flux. Myocardial infarction in an acute setting of IR was examined via comparing loss vs. gain of function experiments in microRNA-210-deficient and wild type mice. Cardiac function was evaluated by echocardiography. Myocardial mitochondria bioenergetics was examined using a Seahorse XF24 Analyzer. MicroRNA-210 deficiency significantly exaggerated cardiac dysfunction up to 6 weeks after myocardial IR in male, but not female, mice. Intravenous injection of microRNA-210 mimic blocked the effect and recovered the increased myocardial IR injury and cardiac dysfunction. Analysis of mitochondrial metabolism revealed that microRNA-210 inhibited mitochondrial oxygen consumption, increased glycolytic activity, and reduced mitochondrial ROS flux in the heart during IR injury. Consistently, inhibition of mitochondrial ROS with MitoQ reversed the effect of microRNA-210 deficiency. Mechanistically, we showed that mitochondrial glycerol-3-phosphate dehydrogenase (GPD2) is a novel target of microRNA-210 in the heart, and loss-of-function and gain-of-function experiments revealed that GPD2 played a key role in the microRNA-210-mediated effect on mitochondrial metabolism and ROS flux in the setting of heart IR injury. Knockdown of GPD2 negated microRNA-210 deficiency-induced increases in mitochondrial ROS production and myocardial infarction, and improved left ventricular fractional shortening and ejection fraction after the IR treatment. MicroRNA-210 targeting GPD2 controls mitochondrial bioenergetics and ROS flux and improves cardiac function in a murine model of myocardial infarction in the setting of IR injury. The findings suggest new insights into the mechanisms and therapeutic targets for treatment of ischemic heart disease.
影响因子：
3.6
作者：
Zhang P;Lv J;Li Y;Zhang L;Xiao D
通讯作者：
Xiao D