Department of Cardiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
Department of Cardiovascular Surgery, Institute of Cardiac Surgery, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai, 200433, China.
Cell Mol Biol Lett. 2022 Oct 8;27(1):85. doi: 10.1186/s11658-022-00379-9.
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.
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.
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.
miR-92a-2-5p plays an important role in cardiac oxidative stress, and may serve as a therapeutic target in DCM.
糖尿病心肌病（DCM）是由糖尿病引起的心脏结构和功能的病理性变化导致的。过度的氧化应激是 DCM 发病机制的一个重要特征。微小 RNA（miRNA）是心血管系统氧化应激的关键调节因子。在本研究中，我们筛选了氧化应激反应 miRNA 在 DCM 发展中的表达。此外，我们旨在探讨 miR-92a-2-5p 预防糖尿病引起的心肌损伤的机制和治疗潜力。
采用高脂饮食联合小剂量链脲佐菌素（30mg/kg）诱导实验性 2 型糖尿病（T2DM）大鼠模型。高糖（33mmol/L）诱导心肌细胞氧化应激损伤。采用实时定量 PCR 筛选氧化应激反应 miRNA。体内通过尾静脉注射 agomiR 或体外转染腺病毒干预 miR-92a-2-5p。
T2DM 组心脏组织 miR-92a-2-5p 表达明显降低。高糖刺激的心肌细胞也检测到 miR-92a-2-5p 表达降低。过表达 miR-92a-2-5p 可减轻心肌细胞氧化应激损伤，表现为谷胱甘肽水平升高，活性氧自由基积累、丙二醛和凋亡水平降低。MAPK 相互作用丝氨酸/苏氨酸激酶 2（MKNK2）被验证为 miR-92a-2-5p 的新靶点。心肌细胞中过表达 miR-92a-2-5p 显著抑制 MKNK2 表达，导致 p38-MAPK 信号转导磷酸化减少，从而减轻心肌细胞氧化应激损伤。此外，miR-92a-2-5p agomiR 的注射显著减轻糖尿病引起的心肌损伤，表现为心肌重构和功能的显著改善。
miR-92a-2-5p 在心脏氧化应激中起重要作用，可能成为 DCM 的治疗靶点。
