Liu Dehui, Zou Shangrong, Li Guangnan, Zhang Qiyu, Chen Chunlin, Li Cuizhi, Song Huafeng, Chen Shaoxian, Wang Jiawen, Wu Yueheng, Liu Youbin
Department of Cardiology, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
Department of Pharmacy, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.
Front Cardiovasc Med. 2022 Feb 24;8:764064. doi: 10.3389/fcvm.2021.764064. eCollection 2021.
Acute myocardial infarction (MI) is one of the leading causes of death in the world, and its pathophysiological mechanisms have not been fully elucidated. The purpose of this study was to investigate the role and mechanism of uncoupling protein 2 (UCP2) after MI in mouse heart. Here, we examined the expression and role of UCP2 in mouse heart 4 weeks after MI. The expression of UCP2 was detected by RT-PCR and western blotting. Cardiac function, myocardial fibrosis, and cardiomyocyte apoptosis were assessed by echocardiography and immunohistochemistry. Phosphatase dynamin-related protein1 (-DRP1) and myocardial fibrosis-related proteins were measured. Cardiomyocytes were exposed to hypoxia for 6 h to mimic the model of MI. Mdivi, an inhibitor of -DRP1, was used to inhibit DRP1-dependent mitochondrial fission. Mitochondrial superoxide, membrane potential, oxygen consumption rate, and cardiomyocyte apoptosis were detected after hypoxia. It is shown mitochondrial superoxide, membrane potential, oxygen consumption rate, and cardiomyocyte apoptosis were dependent on the level of -DRP1. UCP2 overexpression reduced cardiomyocyte apoptosis (fibrosis), improved cardiac function and inhibit the phosphorylation of DRP1 and the ratio of -DRP1/DRP1. However, inhibition of DRP1 by mdivi did not further reduce cell apoptosis rate and cardiac function in UCP2 overexpression group. In addition, bioinformatics analysis, luciferase activity, and western blot assay proved UCP2 was a direct target gene of microRNA-762, a up-regulated microRNA after MI. In conclusion, UCP2 plays a protective role after MI and the mechanism is involved in microRNA-762 upstream and DRP1-dependent mitochondrial fission downstream.
急性心肌梗死（MI）是全球主要的死亡原因之一，其病理生理机制尚未完全阐明。本研究旨在探讨MI后解偶联蛋白2（UCP2）在小鼠心脏中的作用及机制。在此，我们检测了MI后4周小鼠心脏中UCP2的表达及作用。通过RT-PCR和蛋白质印迹法检测UCP2的表达。通过超声心动图和免疫组织化学评估心脏功能、心肌纤维化和心肌细胞凋亡。检测磷酸酶动力相关蛋白1（-DRP1）和心肌纤维化相关蛋白。将心肌细胞暴露于缺氧环境6小时以模拟MI模型。使用Mdivi（一种-DRP1抑制剂）抑制DRP1依赖性线粒体分裂。缺氧后检测线粒体超氧化物、膜电位、耗氧率和心肌细胞凋亡。结果显示线粒体超氧化物、膜电位、耗氧率和心肌细胞凋亡取决于-DRP1的水平。UCP2过表达减少心肌细胞凋亡（纤维化），改善心脏功能，并抑制DRP1的磷酸化以及-DRP1/DRP1的比例。然而，在UCP2过表达组中，Mdivi抑制DRP1并未进一步降低细胞凋亡率和心脏功能。此外，生物信息学分析、荧光素酶活性和蛋白质印迹分析证明UCP2是微小RNA-762的直接靶基因，微小RNA-762是MI后上调的一种微小RNA。总之，UCP2在MI后发挥保护作用，其机制涉及上游的微小RNA-762和下游的DRP1依赖性线粒体分裂。
