MiRNA-27a Transcription Activated by c-Fos Regulates Myocardial Ischemia-Reperfusion Injury by Targeting ATAD3a.

Yandong Bao,Yuxuan Guo,Huimin Yang,Nan Wu,Zeying Zhang,Yuqiong Chen,Hang Yu,Xin Xin,Dalin Jia,Ying Qiao,Hai-Tao Xiao

doi:10.1155/2021/2514947

Abstract

MicroRNA-27a (miR-27a) has been implicated in myocardial ischemia-reperfusion injury (MIRI), but the underlying mechanism is not well understood. This study is aimed at determining the role of miR-27a in MIRI and at investigating upstream molecules that regulate miR-27a expression and its downstream target genes. miR-27a expression was significantly upregulated in myocardia exposed to ischemia/reperfusion (I/R) and cardiomyocytes exposed to hypoxia/reoxygenation (H/R). c-Fos could regulate miR-27a expression by binding to its promoter region. Moreover, overexpression of miR-27a led to a decrease in cell viability, an increase in LDH and CK-MB secretion, and an increase in apoptosis rates. In contrast, suppression of miR-27a expression resulted in the opposite effects. ATPase family AAA-domain-containing protein 3A (ATAD3a) was identified as a target of miR-27a. miR-27a regulated the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and H/R-induced apoptosis via the regulation of ATAD3a. It was found that inhibiting miR-27a in vivo by injecting a miR-27a sponge could ameliorate MIRI in an isolated rat heart model. In conclusion, our study demonstrated that c-Fos functions as an upstream regulator of miR-27a and that miR-27a regulates the translocation of AIF from the mitochondria to the nucleus by targeting ATAD3a, thereby contributing to MIRI. These findings provide new insight into the role of the c-Fos/miR-27a/ATAD3a axis in MIRI.

Highlights

With the dramatic changes in lifestyle and diet that have occurred in modern society, coronary artery disease (CAD) has gradually become one of the major diseases that seriously threaten the lives and health of people worldwide [1]
We found that c-Fos activated the transcription of miR-27a and that miR-27a further regulated the ischemia-reperfusion-induced apoptosis of cardiomyocytes by modulating the translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus by targeting ATPase family AAA-domain-containing protein 3A (ATAD3a)
The results showed that overexpression of miR-27a led to a decrease in cell viability (Figure 3(c)), an increase in lactate dehydrogenase (LDH) (Figure 3(d)) and creatine kinase-MB (CK-MB) (Figure 3(e)) secretion, and an increase in apoptosis (Figure 3(f)) in the cardiomyocytes subjected to H/R

Summary

Introduction

With the dramatic changes in lifestyle and diet that have occurred in modern society, coronary artery disease (CAD) has gradually become one of the major diseases that seriously threaten the lives and health of people worldwide [1]. Severe stenosis or acute occlusion of the coronary arteries can cause myocardial ischemia and even myocardial necrosis. A common approach for treating patients with acute myocardial infarction (AMI) is reconstituting the myocardial blood supply as quickly as possible through the implementation of myocardial reperfusion therapy [2, 3], which includes percutaneous coronary intervention, coronary artery bypass grafting, and thrombolytic therapy. During the implementation of myocardial reperfusion therapy, the rapid recovery of the blood supply to the ischemic myocardium does not ameliorate myocardial damage and causes extramyocardial insult, which is termed myocardial ischemiareperfusion injury (MIRI) [4]. The occurrence of MIRI is difficult to predict in advance, and once it occurs, it greatly reduces the clinical benefit of myocardial reperfusion therapy [5].

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Results

Conclusion