Zhang Jiefang, Wu Lili, Li Zhengwei, Fu Guosheng
Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University of MedicineHangzhou 310016, Zhejiang, PR China.
Am J Transl Res. 2017 Apr 15;9(4):1822-1833. eCollection 2017.
MicroRNAs (miRNAs) are noncoding single-stranded RNAs of ~22 nucleotides suppressing a wide range of gene expression by direct degradation or translational inhibition of their target mRNAs. Acute myocardial infarction (AMI), a common cardiovascular disease mainly induced by coronary artery occlusion, can lead to the development of heart failure. Several recent findings have indicated that miRNAs might play vital roles in AMI, and some miRNAs have even been proposed as potential candidates for intervening AMI. However, the pathophysiological functions of miRNAs implicated in MI are still largely unidentified. Here, we show that miR-1231 is overexpressed both in human hearts after MI insults and in rat hearts with experimental MI compared with their healthy counterparts. Next, by using predictive strategy and gene expression array, cacna2d2 is identified as the target of miR-1231. In human and rat ischemic hearts, cacna2d2 expression is indeed suppressed by miR-1231. In addition, the inhibition of miR-1231 ameliorates arrhythmias in rat MI hearts; conversely, the forced overexpression of miR-1231 promotes arrhythmias. Furthermore, cacna2d2 knockdown alone induced arrhythmias in ischemic hearts, despite knockdown of miR-1231. Thus, these results indicate that miR-1231 exacerbates arrhythmia by inhibiting cacna2d2 in ischemic heart, which shed light on the important arrhythmogenic function of miR-1231 in MI and suggest it may serve as a potential antiarrhythmic target.
微小RNA（miRNA）是约22个核苷酸的非编码单链RNA，通过直接降解或抑制其靶mRNA的翻译来抑制广泛的基因表达。急性心肌梗死（AMI）是一种主要由冠状动脉闭塞引起的常见心血管疾病，可导致心力衰竭的发生。最近的一些研究结果表明，miRNA可能在AMI中发挥重要作用，甚至有一些miRNA被提议作为干预AMI的潜在候选物。然而，与心肌梗死相关的miRNA的病理生理功能仍 largely未被确定。在此，我们表明，与健康对照相比，miR-1231在心肌梗死损伤后的人心脏和实验性心肌梗死的大鼠心脏中均过表达。接下来，通过使用预测策略和基因表达阵列，cacna2d2被确定为miR-1231的靶标。在人和大鼠的缺血心脏中，cacna2d2的表达确实被miR-1231抑制。此外，抑制miR-1231可改善大鼠心肌梗死心脏中的心律失常；相反，强制过表达miR-1231会促进心律失常。此外，单独敲低cacna2d2也会在缺血心脏中诱导心律失常，尽管同时敲低了miR-1231。因此，这些结果表明，miR-1231通过抑制缺血心脏中的cacna2d2来加重心律失常，这揭示了miR-1231在心肌梗死中的重要致心律失常功能，并表明它可能作为一个潜在的抗心律失常靶点。
