Mir-24 regulates junctophilin-2 expression in cardiomyocytes.
Mir-24 regulates junctophilin-2 expression in cardiomyocytes.
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Mir-24 调节心肌细胞中的 Junctophilin-2 表达
DOI：
10.1161/circresaha.112.277418
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发表时间：
2012-09-14
影响因子：
20.1
通讯作者：
Wang SQ
中科院分区：
文献类型：
--
作者：
Xu M;Wu HD;Li RC;Zhang HB;Wang M;Tao J;Feng XH;Guo YB;Li SF;Lai ST;Zhou P;Li LL;Yang HQ;Luo GZ;Bai Y;Xi JJ;Gao W;Han QD;Zhang YY;Wang XJ;Meng X;Wang SQ
理由：衰竭的心肌细胞表现为兴奋-收缩（E-C）耦合效率降低。连接蛋白2 （JP2）是一种将肌浆网锚定在t小管上的蛋白，其下调已被确定为E-C偶联缺陷的主要机制。然而，JP2的调控机制尚不清楚。目的：探讨microrna是否调控JP2的表达。方法和结果：生物信息学分析预测了JP2 mRNA 3 ' -非翻译区miR-24的2个潜在结合位点。荧光素酶测定证实miR-24通过结合这些位点抑制JP2的表达。在主动脉瓣狭窄模型中，miR-24在衰竭心肌细胞中上调。腺病毒导向的心肌细胞中miR-24的过表达降低了JP2的表达，降低了Ca2+的瞬态振幅和E-C偶联增益。结论：mir -24介导的JP2表达抑制为心脏细胞E-C偶联调控提供了一种新的分子机制，提示了治疗心力衰竭的新靶点。
Rationale: Failing cardiomyocytes exhibit decreased efficiency of excitation-contraction (E-C) coupling. The downregulation of junctophilin-2 (JP2), a protein anchoring the sarcoplasmic reticulum to T-tubules, has been identified as a major mechanism underlying the defective E-C coupling. However, the regulatory mechanism of JP2 remains unknown. Objective: To determine whether microRNAs regulate JP2 expression. Methods and Results: Bioinformatic analysis predicted 2 potential binding sites of miR-24 in the 3′-untranslated regions of JP2 mRNA. Luciferase assays confirmed that miR-24 suppressed JP2 expression by binding to either of these sites. In the aortic stenosis model, miR-24 was upregulated in failing cardiomyocytes. Adenovirus-directed overexpression of miR-24 in cardiomyocytes decreased JP2 expression and reduced Ca2+ transient amplitude and E-C coupling gain. Conclusions: MiR-24–mediated suppression of JP2 expression provides a novel molecular mechanism for E-C coupling regulation in heart cells and suggests a new target against heart failure.