lncRNA H19 Alleviated Myocardial I/RI via Suppressing miR-877-3p/Bcl-2-Mediated Mitochondrial Apoptosis
lncRNA H19 Alleviated Myocardial I/RI via Suppressing miR-877-3p/Bcl-2-Mediated Mitochondrial Apoptosis
复制标题
lncRNA H19 通过抑制 miR-877-3p/Bcl-2 介导的线粒体凋亡减轻心肌 I/RI
DOI：
10.1016/j.omtn.2019.05.031
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发表时间：
2019-09-06
影响因子：
8.8
通讯作者：
Lu, Yanjie
中科院分区：
文献类型：
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作者：
Li, Xin;Luo, Shenjian;Lu, Yanjie
缺血性心脏病是世界上发病率和死亡率最高的疾病。尽管心脏研究取得了很大的进展，但目前对心肌缺血再灌注损伤(I/RI)的治疗仍不尽如人意。本研究旨在探讨长非编码RNA(LncRNA)H19在心肌I/RI调节中的作用。我们发现H19在H_2O_2处理的小鼠I/R心脏和心肌细胞中的表达下调。H19过表达可减轻H_2O_2诱导的小鼠心肌I/RI和心肌细胞损伤。我们发现H19作为miR-877-3p的竞争内源RNA，通过碱基配对机制降低miR-877-3p的表达。同时，miR-877-3p在H_2O_2处理的心肌细胞和小鼠缺血再灌注(I/R)心脏中表达上调。MIR-877-3p加重心肌I/RI和心肌细胞凋亡。我们进一步建立了Bcl2作为miR-877-3p的下游靶点。MIR-877-3P抑制Bcl2的mRNA和蛋白表达。此外，H19还可降低心肌I/RI小鼠Bcl2/Bax的基因表达和蛋白水平，降低细胞色素c的释放，降低caspase-9和caspase-3的活性，这一作用可被miR877-3p所抵消。综上所述，H19/miR-877-3p/Bcl2通路参与了心肌I/RI过程中线粒体凋亡的调控，为研究心肌I/RI调控的分子机制提供了新的思路。
Ischemic cardiac disease is the leading cause of morbidity and mortality in the world. Despite the great efforts and progress in cardiac research, the current treatment of cardiac ischemia reperfusion injury (I/RI) is still far from being satisfactory. This study was performed to investigate the role of long non-coding RNA (lncRNA) H19 in regulating myocardial I/RI. We found that H19 expression was downregulated in the I/R hearts of mice and cardiomyocytes treated with H2O2. Overexpression of H19 alleviated myocardial I/RI of mice and cardiomyocyte injury induced by H2O2. We found that H19 functioned as a competing endogenous RNA of miR-877-3p, which decreased the expression of miR-877-3p through the base-pairing mechanism. In parallel, miR-877-3p was upregulated in H2O2-treated cardiomyocytes and mouse ischemia reperfusion (I/R) hearts. miR-877-3p exacerbated myocardial I/RI and cardiomyocyte apoptosis. We further established Bcl-2 as a downstream target of miR-877-3p. miR-877-3p inhibited the mRNA and protein expression of Bcl-2. Furthermore, H19 decreased the Bcl-2/Bax ratio at mRNA and protein levels, cytochrome c release, and activation of caspase-9 and caspase-3 in myocardial I/RI mice, which were canceled by miR877-3p. In summary, the H19/miR-877-3p/Bcl-2 pathway is involved in regulation of mitochondrial apoptosis during myocardial I/RI, which provided new insight into molecular mechanisms underlying regulation of myocardial I/RI.