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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Downregulation of connexin43 by microRNA-130a in cardiomyocytes results in cardiac arrhythmias
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Downregulation of connexin43 by microRNA-130a in cardiomyocytes results in cardiac arrhythmias

机译：microRNA-130a在心肌细胞中下调connexin43导致心律失常

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摘要

MicroRNAs (miRNAs) are now recognized as critical regulators of diverse physiological and pathological processes; however, studies of miRNAs and arrhythmogenesis remain sparse. Connexin43 (Cx43), a major cardiac gap junction protein, has elicited great interest in its role in arrhythmias. Additionally, Cx43 was a potential target for miR-130a as predicted by several computational algorithms. This study investigates the effect of miR-130a overexpression in the adult heart and its effect on cardiac rhythm. Using a cardiac-specific inducible system, transgenic mice demonstrated both atrial and ventricular arrhythmias. We performed ventricular-programmed electrical stimulation and found that the aMHC-miR130a mice developed sustained ventricular tachycardia beginning 6 weeks after overexpression. Western blot analysis demonstrated a steady decline in Cx43 after 2 weeks of overexpression with over a 90% reduction in Cx43 levels by 10 weeks. Immunofluorescent staining confirmed a near complete loss of Cx43 throughout the heart. To validate Cx43 as a direct target of miR-130a, we performed in vitro target assays in 3T3 fibroblasts and HL-1 cardiomyocytes, both known to endoge-nously express miR-130a. Using a luciferase reporter fused to the 3'UTR of Cx43, we found a 52.9% reduction in luciferase activity in 3T3 cells (p < 0.0001) and a 47.6% reduction in HL-1 cells (p = 0.0056) compared to controls. Addition of an antisense miR-130a inhibitor resulted in a loss of inhibitory activity of the Cx43 3'UTR reporter. We have identified an unappreciated role for miR-130a as a direct regulator of Cx43. Overexpression of miR-130a may contribute importantly to gap junction remodeling and to the pathogenesis of atrial and ventricular arrhythmias.
机译：MicroRNA（miRNA）现在被认为是多种生理和病理过程的关键调节因子。但是，关于miRNA和心律不齐的研究仍然很少。连接蛋白43（Cx43），一种主要的心脏间隙连接蛋白，引起了人们对其在心律失常中的作用的极大兴趣。另外，Cx43是miR-130a的潜在靶标，正如几种计算算法所预测的那样。这项研究调查了miR-130a在成年心脏中的过度表达及其对心律的影响。使用心脏特异性诱导系统，转基因小鼠表现出房性和室性心律失常。我们进行了心室程序性电刺激，发现aMHC-miR130a小鼠在过度表达后6周开始出现持续性室性心动过速。 Western印迹分析表明，过表达2周后Cx43持续下降，到10周时Cx43水平降低了90％以上。免疫荧光染色证实整个心脏中Cx43几乎完全丧失。为了验证Cx43是miR-130a的直接靶标，我们在3T3成纤维细胞和HL-1心肌细胞中进行了体外靶标测定，这两个方法均能内源性表达miR-130a。使用与Cx43的3'UTR融合的荧光素酶报告基因，我们发现3T3细胞中的荧光素酶活性降低了52.9％（p <0.0001），而HL-1细胞则降低了47.6％（p = 0.0056）。添加反义miR-130a抑制剂会导致Cx43 3'UTR报告基因的抑制活性丧失。我们已经确定了miR-130a作为Cx43的直接调节剂的作用并不明显。 miR-130a的过度表达可能对间隙连接重塑以及房性和室性心律失常的发病机制起重要作用。

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