MiR-378a-3p inhibits ischemia/reperfusion-induced apoptosis in H9C2 cardiomyocytes by targeting TRIM55 via the DUSP1-JNK1/2 signaling pathway.

Jiaying Tan,Tao Sun,Hechen Zhu,Ye Gong,Jun Shen,Huigeng Zhu,Junping Li,Shan Lin,Gang Wu

doi:10.18632/aging.103106

Abstract

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.

Highlights

Ischemic heart disease is the leading cause of death in humans worldwide and the morbidity and mortality caused by myocardial ischemia have increased yearly
We found that I/R-induced H9C2 cardiomyocytes transfected with the miR-378a3p mimic showed a significant increase in miR-378a-3p expression (2.31-fold), while transfection with the miR378a-3p inhibitor led to a 44.7% decrease in miR-378a3p expression when compared with the miR-378a-3p negative control (NC) (Figure 1B)
I/R-induced H9C2 cardiomyocytes transfected with a miR-378a-3p mimic showed a 58.6% decrease in cell apoptosis, while transfection with a miR-378a-3p inhibitor led to a 38.3% increase in cell apoptosis when compared to the NC

Summary

Introduction

Ischemic heart disease is the leading cause of death in humans worldwide and the morbidity and mortality caused by myocardial ischemia have increased yearly. Clinical treatments such as thrombolytic therapy or early coronary intervention in the ischemic site can effectively improve myocardial ischemia or necrosis [1, 2]. MicroRNAs (miRNA, miR) are highly conserved endogenous small non-coding RNAs which are involved in the post-transcriptional regulation of genes and play important roles in cell proliferation, differentiation, and apoptosis, as well as oxidative stress [7]. The role of miR-378a-3p in the regulation of apoptosis during myocardial I/R injury remains unclear

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Results

Conclusion