State Key Laboratory of Biomembrane and Membrane Biotechnology, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Third Hospital, College of Engineering and College of Life Sciences, Peking University, China.
Circ Res. 2012 Sep 14;111(7):837-41. doi: 10.1161/CIRCRESAHA.112.277418. Epub 2012 Aug 13.
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.
To determine whether microRNAs regulate JP2 expression.
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 Ca(2+) transient amplitude and E-C coupling gain.
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.
衰竭的心肌细胞表现出兴奋-收缩（E-C）偶联效率降低。衔接蛋白-2（JP2）的下调，这种蛋白将肌浆网锚定到 T 小管，已被确定为导致 E-C 偶联缺陷的主要机制。然而，JP2 的调节机制仍不清楚。
确定 microRNAs 是否调节 JP2 的表达。
生物信息学分析预测 JP2 mRNA 的 3'-非翻译区有 miR-24 的 2 个潜在结合位点。荧光素酶测定证实 miR-24 通过与这些位点中的任一个结合来抑制 JP2 的表达。在主动脉瓣狭窄模型中，衰竭的心肌细胞中 miR-24 上调。在心肌细胞中，腺病毒介导的 miR-24 过表达降低了 JP2 的表达，减少了 Ca(2+)瞬变幅度和 E-C 偶联增益。
miR-24 介导的 JP2 表达抑制为心脏细胞中 E-C 偶联调节提供了一个新的分子机制，并为心力衰竭提供了一个新的治疗靶点。
