Su Xiaomin, Lv Lifang, Li Yue, Fang Ruonan, Yang Rui, Li Chao, Li Tianyu, Zhu Di, Li Xuelian, Zhou Yuhong, Shan Hongli, Liang Haihai
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China; Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China; The Centre of Functional Experiment Teaching, Department of Basic Medicine, Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.
Mol Ther Nucleic Acids. 2020 Jun 5;20:841-850. doi: 10.1016/j.omtn.2020.05.002. Epub 2020 May 8.
Acute myocardial infarction (AMI) is the leading cause of death worldwide. Identifying the pathways that block cardiac cell death is a therapeutic strategy for ischemic heart disease. We found that long noncoding RNA (lncRNA) myocardial infarction-regulatory factor (MIRF) promoted ischemic myocardial injury by regulating autophagy through targeting miR-26a. However, the role of MIRF-miR-26a in apoptosis during AMI has not been delineated. In this study, we found the downregulation of miR-26a both in the heart of myocardial infarction (MI) mice and in HO-treated cardiomyocytes. miR-26a silencing resulted in apoptosis, whereas overexpression of miR-26a attenuated HO-induced apoptosis through promoting mitochondrial ATP content and increasing mitochondrial membrane potential (MMP). Moreover, forced expression of miR-26a protected against MI-induced cardiac injury and attenuated cardiac apoptosis. Further studies showed that miR-26a inhibited apoptosis through regulation of Bak1. Furthermore, MIRF decreased ATP content and MMP through regulating miR-26a, which then promoted the cardiomyocyte apoptosis. In contrast, deficiency of MIRF promoted mitochondrial ATP content and increased MMP, and then inhibited MI or HO-induced cardiac apoptosis, which was abolished by miR-26a inhibitor. Taken together, these results suggested that MIRF contributed to cardiomyocyte apoptosis through modulating Bak1 by regulation of miR-26a, which can be a potential therapeutic target for the treatment of ischemic heart disease.
急性心肌梗死（AMI）是全球范围内主要的死亡原因。确定阻止心脏细胞死亡的途径是缺血性心脏病的一种治疗策略。我们发现长链非编码RNA（lncRNA）心肌梗死调节因子（MIRF）通过靶向miR-26a调节自噬，从而促进缺血性心肌损伤。然而，MIRF-miR-26a在AMI期间细胞凋亡中的作用尚未明确。在本研究中，我们发现miR-26a在心肌梗死（MI）小鼠心脏和HO处理的心肌细胞中均下调。miR-26a沉默导致细胞凋亡，而miR-26a过表达通过促进线粒体ATP含量和增加线粒体膜电位（MMP）减轻HO诱导的细胞凋亡。此外，强制表达miR-26a可预防MI诱导的心脏损伤并减轻心脏细胞凋亡。进一步研究表明，miR-26a通过调节Bak1抑制细胞凋亡。此外，MIRF通过调节miR-26a降低ATP含量和MMP，进而促进心肌细胞凋亡。相反，MIRF缺陷促进线粒体ATP含量并增加MMP，进而抑制MI或HO诱导的心脏细胞凋亡，而miR-26a抑制剂可消除这种抑制作用。综上所述，这些结果表明MIRF通过调节miR-26a调控Bak1，从而促进心肌细胞凋亡，这可能是治疗缺血性心脏病的一个潜在治疗靶点。
