Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Cell Death Dis. 2017 Jul 13;8(7):e2929. doi: 10.1038/cddis.2017.321.
We previously established a rat model of diabetic cardiomyopathy (DCM) and found that the expression of long non-coding RNA myocardial infarction-associated transcript (MIAT) was significantly upregulated. The present study was aimed to determine the pathologic role of MIAT in the development of DCM. MIAT knockdown was found to reduce cardiomyocyte apoptosis and improve left ventricular function in diabetic rats. High glucose could increase MIAT expression and induce apoptosis in cultured neonatal cardiomyocytes. The results of luciferase reporter assay and RNA immunoprecipitation assay revealed that MIAT was targeted by miR-22-3p in an AGO2-dependent manner. In addition, the 3'-untranslated region of DAPK2 was fused to the luciferase coding region and transfected into HEK293 cells with miR-22-3p mimic, and the results showed that DAPK2 was a direct target of miR-22-3p. Our findings also indicated that MIAT overexpression could counteract the inhibitory effect of miR-22-3p on DAPK2. Moreover, MIAT knockdown was found to reduce DAPK2 expression and inhibit apoptosis in cardiomyocytes exposed to high glucose. In conclusion, our study demonstrates that MIAT may function as a competing endogenous RNA to upregulate DAPK2 expression by sponging miR-22-3p, which consequently leads to cardiomyocyte apoptosis involved in the pathogenesis of DCM.
我们之前建立了糖尿病心肌病（DCM）大鼠模型，发现长链非编码 RNA 心肌梗塞相关转录物（MIAT）的表达明显上调。本研究旨在确定 MIAT 在 DCM 发展中的病理作用。研究发现，MIAT 敲低可减少糖尿病大鼠心肌细胞凋亡，改善左心室功能。高糖可增加 MIAT 的表达并诱导培养的新生大鼠心肌细胞凋亡。荧光素酶报告基因检测和 RNA 免疫沉淀实验结果表明，MIAT 是AGO2 依赖性 miR-22-3p 的靶基因。此外，将 DAPK2 的 3'非翻译区与荧光素酶编码区融合，并转染 miR-22-3p 模拟物至 HEK293 细胞，结果表明 DAPK2 是 miR-22-3p 的直接靶基因。我们的研究结果还表明，MIAT 过表达可抵消 miR-22-3p 对 DAPK2 的抑制作用。此外，研究发现 MIAT 敲低可降低高糖诱导的心肌细胞中 DAPK2 的表达并抑制细胞凋亡。综上所述，本研究表明，MIAT 可能通过海绵吸附 miR-22-3p 而上调 DAPK2 表达，从而导致参与 DCM 发病机制的心肌细胞凋亡，作为竞争性内源 RNA 发挥作用。
