miR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway
miR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway
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DOI：
10.18632/aging.103106
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发表时间：
2020-05-31
期刊：
影响因子：
5.2
通讯作者：
Sun, Tao
中科院分区：
文献类型：
--
作者：
Tan, Jiaying;Shen, Jun;Sun, Tao
MicroRNAs （miRNAs）通过调节基因表达参与许多病理和生物学过程，如缺血/再灌注（I/R）损伤。越来越多的证据表明，miR-378a-3p可能对缺血性心脏病提供潜在的心脏保护作用。细胞凋亡是I/R损伤的重要机制。因此，本研究评估了miR-378a-3p对I/R损伤后H9C2心肌细胞凋亡的保护作用及其潜在机制。我们发现I/ r诱导的H9C2心肌细胞miR-378a-3p表达降低，而miR-378a-3p模拟物抑制细胞凋亡、JNK1/2激活、PARP和caspase-3的裂解以及Bax/Bcl-2比值，但增加DUSP1表达，随后抑制JNK1/2磷酸化。TRIM55被证明是miR-378a-3p的靶标，其下调抑制了miR-378a-3p抑制剂诱导的细胞凋亡和JNK1/2活化的增加。TRIM55通过使DUSP1泛素化抑制DUSP1蛋白的表达。此外，DUSP1过表达抑制TRIM55过表达诱导的细胞凋亡和JNK1/2活化的增加。随后在大鼠心肌I/R模型中证实了miR-378a-3p的保护作用，心肌细胞凋亡减少，TRIM55表达减少，JNK1/2激活减少。综上所述，这些结果表明miR-378a-3p可能通过TRIM55/DUSP1/JNK信号传导抑制I/ r诱导的心肌细胞凋亡。
MicroRNAs (miRNAs) are involved in many pathological and biological processes, such as ischemia/reperfusion (I/R) injury by modulating gene expression. Increasing evidence indicates that miR-378a-3p might provide a potential cardioprotective effect against ischemic heart disease. Cell apoptosis is a crucial mechanism in I/R injury. As such, this study evaluated the protective effects and underlying mechanisms of action of miR-378a-3p on H9C2 cardiomyocyte apoptosis following I/R injury. We found that I/R-induced H9C2 cardiomyocytes exhibited a decrease in miR-378a-3p expression, while treatment with a miR-378a-3p mimic suppressed cell apoptosis, JNK1/2 activation, cleavage of PARP and caspase-3, and Bax/Bcl-2 ratio but increased DUSP1 expression, which subsequently inhibited JNK1/2 phosphorylation. TRIM55 was shown to be a target of miR-378a-3p and its downregulation inhibited the miR-378a-3p inhibitor-induced increase in cell apoptosis and JNK1/2 activation. TRIM55 inhibited DUSP1 protein expression through ubiquitination of DUSP1. Moreover, DUSP1 overexpression inhibited the TRIM55 overexpression-induced increase in cell apoptosis and JNK1/2 activation. The protective effect of miR-378a-3p was subsequently confirmed in a rat myocardial I/R model, as evidenced by a decrease in cardiomyocyte apoptosis of cardiomyocytes, TRIM55 expression, and JNK1/2 activation. Taken together, these results suggest that miR-378a-3p may protect against I/R-induced cardiomyocyte apoptosis via TRIM55/DUSP1/JNK signaling.