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

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.

糖尿病性心肌病（DCM）最初的特征是早期舒张功能障碍、左心室重构、肥厚以及心肌纤维化，最终表现为临床心力衰竭。微小核糖核酸（miRNAs），内源性小分子非编码核糖核酸，在糖尿病（DM）中发挥重要作用。然而，miRNAs与DCM发展相关的机制在很大程度上仍然未知。在此，我们旨在阐明微小RNA - 340 - 5p在db/db小鼠DCM中的潜在作用机制，db/db小鼠是一种常用的2型糖尿病及导致心力衰竭的糖尿病并发症模型。我们首先证明了在糖尿病条件下，小鼠心脏组织和心肌细胞中miR - 340 - 5p的表达显著增加。miR - 340 - 5p的过表达加剧了DCM，这在db/db小鼠中表现为广泛的心肌纤维化和更严重的功能障碍，具体表现为凋亡心肌细胞增加、活性氧（ROS）产生增多以及线粒体功能受损。通过 Tough Decoy（TUD）载体抑制miR - 340 - 5p有利于防止ROS产生和细胞凋亡，从而挽救糖尿病性心肌病。我们确定髓细胞白血病1（Mcl - 1）是miR - 340 - 5p的一个主要靶基因，并表明Mcl - 1的抑制导致线粒体功能丧失增加、氧化应激和心肌细胞凋亡，从而导致糖尿病小鼠心脏功能障碍。总之，我们的结果表明miR - 340 - 5p在DCM的发展中起关键作用，可作为治疗干预的靶点。