MicroRNA-155 Promotes Myocardial Infarction-Induced Apoptosis by Targeting RNA-Binding Protein QKI.

Xiu-Qing Yan,Hui-Bin Liu,Jing Guo,Juan Hu,Jie Yu,Zhi-Min Du,Ye Yuan,Chuan Sun

doi:10.1155/2019/4579806

Abstract

Acute myocardial infarction (AMI) is the leading cause of sudden death worldwide. MicroRNA-155 (miR-155) has been reported to target antiapoptotic genes in various diseases models, but the functional role of miR-155 in response to MI injury needs further investigations. This study investigated the role of miR-155 in myocardial ischemia injury. TUNEL and flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect protein expressions of Bcl-2, XIAP, Bax, and caspase-3. qRT-PCR was used to quantify miRNA levels. We showed that miR-155 was dynamically elevated in murine hearts subjected to MI and in neonatal rat ventricular cardiomyocyte (NRVM) injury induced by hydrogen peroxide (H2O2). In response to H2O2, the silencing of miR-155 using AMO-155 (antisense inhibitor oligodeoxyribonucleotides) significantly increased cell viability and reduced cell apoptosis. Moreover, AMO-155 reversed the H2O2-induced downregulation of Bcl-2 and XIAP and upregulation of Bax and cleaved-caspase-3. Further study revealed that AMO-155 resulted in a decrease of H2O2-induced JC-1-labelled monomeric cell number. In addition, AMO-155 markedly decreased infarct size, ameliorated impaired cardiac function, and significantly reduced apoptotic cell percentages in MI mice heart. The RNA-binding protein Quaking (QKI) was predicted as a target gene of miR-155 through bioinformatic analysis, and AMO-155 attenuated the downregulation of QKI in H2O2-treated cardiomyocytes and MI mice heart. Knockdown of QKI by siRNA abolished the antiapoptotic effects of AMO-155. Taken together, miR-155 is upregulated in the MI heart and NRVMs in response to H2O2 stress, and downregulating of miR-155 protects cardiomyocytes against apoptosis. Mechanistically, it is probably due to the repression of QKI signaling pathway.

Highlights

Acute myocardial infarction (AMI) can lead to left ventricular dilatation, heart failure, and sudden cardiac death, resulting in high morbidity and mortality worldwide [1]
Neonatal rat ventricular cardiomyocytes (NRVMs) were isolated from the ventricles of neonatal Sprague-Dawley rats (1-3 days old), which were obtained from the Experimental Animal Center of the Second Affiliated Hospital of Harbin Medical University, China
In line with the results shown above, miR-155 expression was increased by 66% in NRVMs after 100 μM H2O2 treatment (Figure 1(d))

Summary

Introduction

Acute myocardial infarction (AMI) can lead to left ventricular dilatation, heart failure, and sudden cardiac death, resulting in high morbidity and mortality worldwide [1]. Numerous experimental and clinical studies have shown that cardiomyocyte apoptosis occurs in the border zone close to myocardial infarcted area. It was usually caused by oxidative stress, ischemia, and hypoxic injury and reperfusion, subsequently aggravating cardiac dysfunction [2,3,4,5]. Studies suggested that miR-155 is involved in regulating cardiac fibrosis via the TGF-β1/ Smad signaling pathway [10]. The RNA-binding protein Quaking (QKI) has high expression in the adult heart and other organs [11, 12], which is involved in miRNA metabolic processing [13, 14]. The downregulation of miR-155 may provide a therapeutic target for MI in mice

Materials and Methods

Results

Discussion

Findings

Conclusions