Therapeutic overexpression of miR-92a-2-5p ameliorated cardiomyocyte oxidative stress injury in the development of diabetic cardiomyopathy

Abstract

Background Diabetic cardiomyopathy (DCM) results from pathological changes in cardiac structure and function caused by diabetes. Excessive oxidative stress is an important feature of DCM pathogenesis. MicroRNAs (miRNAs) are key regulators of oxidative stress in the cardiovascular system. In the present study, we screened for the expression of oxidative stress-responsive miRNAs in the development of DCM. Furthermore, we aimed to explore the mechanism and therapeutic potential of miR-92a-2-5p in preventing diabetes-induced myocardial damage. Methods An experimental type 2 diabetic (T2DM) rat model was induced using a high-fat diet and low-dose streptozotocin (30 mg/kg). Oxidative stress injury in cardiomyocytes was induced by high glucose (33 mmol/L). Oxidative stress-responsive miRNAs were screened by quantitative real-time PCR. Intervention with miR-92a-2-5p was accomplished by tail vein injection of agomiR in vivo or adenovirus transfection in vitro. Results The expression of miR-92a-2-5p in the heart tissues was significantly decreased in the T2DM group. Decreased miR-92a-2-5p expression was also detected in high glucose-stimulated cardiomyocytes. Overexpression of miR-92a-2-5p attenuated cardiomyocyte oxidative stress injury, as demonstrated by increased glutathione level, and reduced reactive oxygen species accumulation, malondialdehyde and apoptosis levels. MAPK interacting serine/threonine kinase 2 (MKNK2) was verified as a novel target of miR-92a-2-5p. Overexpression of miR-92a-2-5p in cardiomyocytes significantly inhibited MKNK2 expression, leading to decreased phosphorylation of p38-MAPK signaling, which, in turn, ameliorated cardiomyocyte oxidative stress injury. Additionally, diabetes-induced myocardial damage was significantly alleviated by the injection of miR-92a-2-5p agomiR, which manifested as a significant improvement in myocardial remodeling and function. Conclusions miR-92a-2-5p plays an important role in cardiac oxidative stress, and may serve as a therapeutic target in DCM. Graphical Abstract

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity

“…In a type 2 diabetic rat model, the overexpression of miR-92a-2-5p attenuated oxidative stress. 69 Additionally, transfecting human endothelial progenitor cells from myocardial infarction patients and healthy controls with a miR-324-5p mimic resulted in a significant reduction in ROS levels. 70 miR-181c targets mitochondrial function by altering the expression of mitochondrial genes, such as mt-COX1, a subunit of complex IV of the respiratory chain, leading to increased ROS production.…”

Roles of non-coding RNA in diabetic cardiomyopathy

“…For instance, Zhu et al indicated that overexpression of miR-340-5p [ 59 ] in cardiomyocytes led to increased mitochondrial functional loss, oxidative stress, and cardiomyocyte apoptosis in diabetic mice by targeting myeloid cell leukemia 1(Mcl-1). Yu et al [ 60 ] observed that decreased miR-92a-2-5p expression was also detected in high glucose-induced cardiomyocytes. Overexpression of miR-92a-2-5p ameliorated cardiomyocyte oxidative stress injury, by inhibiting MKNK2 expression and leading to decreased phosphorylation of p38-mitogen-activated protein kinase(MAPK) signaling.…”

Enhanced expression of miR-20a driven by nanog exacerbated the degradation of extracellular matrix in thoracic aortic dissection

“…MicroRNAs (miRNAs) are a class of small non-coding RNAs that play essential roles in diverse biological processes. As crucial epigenetic modulators, miRNAs can regulate the expression of target genes by binding to 3′ untranslated region (3’ UTR) without sequence alteration [ 15 , 16 ]. The miR-17-92 cluster is a highly conserved miRNA cluster containing six members (miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1) that collectively participate in a variety of physiological and pathological processes [ 17 ].…”