MiR-340-5p Mediates Cardiomyocyte Oxidative Stress in Diabetes-Induced Cardiac Dysfunction by Targeting Mcl-1.

Yinghong Zhu,Lin Chen,Yingyi Xu,Qiushi Li,Jing Zhou,Dejiang Wang,Long Chen,Yi Yan,Pengfei Zuo,Lan Jiang,Ting Li,Xuewen Yang,Yuli Huang

doi:10.1155/2022/3182931

Abstract

Diabetic cardiomyopathy (DCM) is initially characterized by early diastolic dysfunction, left ventricular remodeling, hypertrophy, and myocardial fibrosis, and it is eventually characterized by clinical heart failure. MicroRNAs (miRNAs), endogenous small noncoding RNAs, play significant roles in diabetes mellitus (DM). However, it is still largely unknown about the mechanism that links miRNAs and the development of DCM. Here, we aimed to elucidate the mechanism underlying the potential role of microRNA-340-5p in DCM in db/db mouse, which is a commonly used model of type 2 DM and diabetic complications that lead to heart failure. We first demonstrated that miR-340-5p expression was dramatically increased in heart tissues of mice and cardiomyocytes under diabetic conditions. Overexpression of miR-340-5p exacerbated DCM, which was reflected by extensive myocardial fibrosis and more serious dysfunction in db/db mice as represented by increased apoptotic cardiomyocytes, elevated ROS production, and impaired mitochondrial function. Inhibition of miR-340-5p by a tough decoy (TUD) vector was beneficial for preventing ROS production and apoptosis, thus rescuing diabetic cardiomyopathy. We identified myeloid cell leukemia 1 (Mcl-1) as a major target gene for miR-340-5p and showed that the inhibition of Mcl-1 was responsible for increased functional loss of mitochondria, oxidative stress, and cardiomyocyte apoptosis, thereby caused cardiac dysfunction in diabetic mice. In conclusion, our results showed that miR-340-5p plays a crucial role in the development of DCM and can be targeted for therapeutic intervention.

Highlights

Diabetic cardiomyopathy (DCM) is one of the common complications in people with diabetes mellitus (DM), leading to cardiac dysfunction that develops in the absence of other risk factors like hypertension, coronary artery disease, and valvular heart disease [1, 2]
We demonstrated that the treatment of recombinant adeno-associated virus of type-9 containing miR340-5p tough decoy (TUD) rescued cardiac dysfunction in diabetic db/db mice, which is a potential therapeutic target for DM-associated cardiac dysfunction
Though there is no significant change in wt heart tissues (Supplementary Figure 2(d)), we found that expression of Bcl-2 was significantly decreased in the diabetic hearts transfected with miR-340-5p and this decrease was reversed in the miR-340-5p TUD-treated hearts, whereas Bax protein levels showed the reverse trend

Summary

Introduction

Diabetic cardiomyopathy (DCM) is one of the common complications in people with diabetes mellitus (DM), leading to cardiac dysfunction that develops in the absence of other risk factors like hypertension, coronary artery disease, and valvular heart disease [1, 2]. The etiology of DCM is multifactorial, recent studies have indicated several pathogenic changes including increased advanced glycation end-products, fibrosis, oxidative stress, impaired Ca2+ balance, impaired mitochondrial function, altered myocardial insulin signaling, and elevated apoptotic and necrotic cell death [3]. A recent study has reported that in the hearts of streptozotocin(STZ-) induced DM mice, 316 significantly changed miRNAs are identified, and interestingly, glycemic control fails to reverse such hyperglycemia-induced miRNA dysregulation in the diabetic hearts, suggesting that the potential association of miRNAs and the development of DCM might be independent of hyperglycemia [7]. A recent study has identified a significant elevation of miRNA-340-5p in the hearts from db/db mice by small RNA sequencing in comparison with wt mice [9], it is still unclear whether increased miR-340-5p levels in the DM heart are associated with the pathological changes in DCM progression. We demonstrated that the treatment of recombinant adeno-associated virus of type-9 (rAAV9) containing miR340-5p tough decoy (TUD) rescued cardiac dysfunction in diabetic db/db mice, which is a potential therapeutic target for DM-associated cardiac dysfunction

Materials and Methods

Results

Discussion

Conclusions

Conflicts of Interest