LncRNA MIAT functions as a competing endogenous RNA to upregulate DAPK2 by sponging miR-22-3p in diabetic cardiomyopathy

Xiang Zhou,Mengchao Jin,Jianchang Chen,Wei Zhang,Xiangqing Kong,Weiting Xu

doi:10.1038/cddis.2017.321

Abstract

We previously established a rat model of diabetic cardiomyopathy (DCM) and found that the expression of long non-coding RNA myocardial infarction–associated transcript (MIAT) was significantly upregulated. The present study was aimed to determine the pathologic role of MIAT in the development of DCM. MIAT knockdown was found to reduce cardiomyocyte apoptosis and improve left ventricular function in diabetic rats. High glucose could increase MIAT expression and induce apoptosis in cultured neonatal cardiomyocytes. The results of luciferase reporter assay and RNA immunoprecipitation assay revealed that MIAT was targeted by miR-22-3p in an AGO2-dependent manner. In addition, the 3′-untranslated region of DAPK2 was fused to the luciferase coding region and transfected into HEK293 cells with miR-22-3p mimic, and the results showed that DAPK2 was a direct target of miR-22-3p. Our findings also indicated that MIAT overexpression could counteract the inhibitory effect of miR-22-3p on DAPK2. Moreover, MIAT knockdown was found to reduce DAPK2 expression and inhibit apoptosis in cardiomyocytes exposed to high glucose. In conclusion, our study demonstrates that MIAT may function as a competing endogenous RNA to upregulate DAPK2 expression by sponging miR-22-3p, which consequently leads to cardiomyocyte apoptosis involved in the pathogenesis of DCM.

Highlights

Diabetic cardiomyopathy (DCM), which is defined as myocardial dysfunction occurring in the absence of coronary artery disease and hypertension, carries a substantial risk for the subsequent development of heart failure.[1]
It has been well documented that Long non-coding RNAs (lncRNAs) have critical roles in the regulation of various cardiovascular diseases, but little is known about the function of lncRNAs in the pathogenesis of DCM, an important cardiovascular complication of diabetes
We established a streptozocin-induced diabetic rat model to investigate the pathologic role of lncRNA myocardial infarction–associated transcript (MIAT) in the development of DCM

Summary

Introduction

Diabetic cardiomyopathy (DCM), which is defined as myocardial dysfunction occurring in the absence of coronary artery disease and hypertension, carries a substantial risk for the subsequent development of heart failure.[1]. Long non-coding RNAs (lncRNAs) represent a class of transcripts longer than 200 nucleotides without protein-coding function. They have critical roles in various biological processes, including gene expression regulation, genomic imprinting, nuclear-cytoplasmic trafficking, RNA splicing and translational control.[3] We previously established a rat model of DCM and performed a microarray to identify the differentially expressed lncRNAs in myocardial tissue. MIAT has been identified as a risk allele for myocardial infarction in a large-scale case–control association study in Japanese subjects.[4] A recent study revealed that MIAT might act as a competing endogenous RNA (ceRNA), and form a feedback loop with vascular endothelial growth factor and miR-150-5p to regulate endothelial cell function.[5]. Using in silico prediction and in vitro functional assays, we found that MIAT could function as a ceRNA to upregulate DAPK2 by sponging miR-22-3p, which contributes to cardiomyocyte apoptosis in DCM

Methods

Results

Conclusion