Xu Chao-Rui, Fang Qiu-Ju
Heilongjiang Province Hospital, Harbin - China.
Heilongjiang Province Hospital - Department of Cardiology for the Elderly, Harbin - China.
Arq Bras Cardiol. 2021 Mar;116(3):415-422. doi: 10.36660/abc.20190529.
It is well-known that insulin resistance and hyperglycemia are important pathological causes for the development of diabetic cardiomyopathy (DCM). However, its precise molecular mechanisms in the pathogenesis of DCM remain unclear.
Recent studies reveal that microRNAs (miRNA) play essential roles in the pathogenesis of DCM. This project aimed to determine the roles of miR-34a and miR-125b in hyperglycemia-induced cardiomyocyte cell death.
Rat primary cardiomyocytes were isolated and exposed to normal and high concentrations of glucose. Cell viability was measured using MTT assay. Expressions of miR-34a and miR-125b were detected by qRT-PCR. Potential targets of miR-34a and miR-125b were predicted from www.Targetscan.org and validated from human heart tissues. A statistical significance of p<0.05 was considered.
The present study shows that miR-34a and miR-125b are downregulated in a human diabetic heart. Moreover, in vitro data from rat primary cardiomyocytes showed that short-term high glucose treatment stimulates miR-34a and miR-125b expressions. Under high glucose, it was found that rat cardiomyocytes displayed increased intracellular glucose metabolism, and glucose uptake and lactate production were significantly increased. It was also found that the key glucose metabolic enzymes, Hexokinase 2 (HK2) and Lactate dehydrogenase-A (LDHA), were direct targets of miR-125b and miR-34a, respectively. Overexpression of miR-125b and miR-34a could prevent hyperglycemia-induced cardiomyocyte cell death. Finally, the restoration of HK2 and LDHA in miR-125b and miR-34a overexpressed cardiomyocytes recovered the cardiomyocytes' sensitivity to hyperglycemia.
Our results proposed a molecular mechanism for the microRNA-mediated diabetic cardiovascular protection and will contribute to developing treatment strategies for diabetes-associated cardiovascular dysfunction.
众所周知，胰岛素抵抗和高血糖是糖尿病性心肌病（DCM）发生发展的重要病理原因。然而，其在DCM发病机制中的确切分子机制仍不清楚。
最近的研究表明，微小RNA（miRNA）在DCM的发病机制中起重要作用。本项目旨在确定miR-34a和miR-125b在高血糖诱导的心肌细胞死亡中的作用。
分离大鼠原代心肌细胞，分别置于正常浓度和高浓度葡萄糖环境中。采用MTT法检测细胞活力。通过qRT-PCR检测miR-34a和miR-125b的表达。从www.Targetscan.org预测miR-34a和miR-125b的潜在靶标，并在人体心脏组织中进行验证。p<0.05被认为具有统计学意义。
本研究表明，miR-34a和miR-125b在人类糖尿病心脏中表达下调。此外，大鼠原代心肌细胞的体外数据显示，短期高糖处理可刺激miR-34a和miR-125b的表达。在高糖环境下，发现大鼠心肌细胞的细胞内葡萄糖代谢增加，葡萄糖摄取和乳酸生成显著增加。还发现关键的葡萄糖代谢酶己糖激酶2（HK2）和乳酸脱氢酶-A（LDHA）分别是miR-125b和miR-34a的直接靶标。miR-125b和miR-34a的过表达可预防高血糖诱导的心肌细胞死亡。最后，在miR-125b和miR-34a过表达的心肌细胞中恢复HK2和LDHA可恢复心肌细胞对高血糖的敏感性。
我们的研究结果提出了一种微小RNA介导的糖尿病心血管保护的分子机制，将有助于制定针对糖尿病相关心血管功能障碍的治疗策略。
