2012年9月14日,，心血管基礎(chǔ)研究的最高專業(yè)期刊Circulation Research以“超快通訊（Ultra-rapid Communication）”的優(yōu)先形式發(fā)表了我院王世強(qiáng)教授實驗室與北醫(yī)三院、中科院遺傳發(fā)育所等單位的合作研究成果：miR-24 抑制junctophilin-2(JP2)的表達(dá)導(dǎo)致心肌細(xì)胞興奮收縮耦聯(lián)減弱,。該期Circulation Research同時配發(fā)了一篇述評,，高度評價該發(fā)現(xiàn)揭示了心力衰竭病理過程的關(guān)鍵調(diào)控機(jī)制。
心力衰竭是多種心臟病的最后階段,，是威脅人類健康和生命的重大疾病之一,。2007年以來，王世強(qiáng)教授實驗室與北醫(yī)三院合作在PLoS Biology和Cardiovascular Research等重要期刊發(fā)表系列論文,，證明細(xì)胞膜鈣通道與肌質(zhì)網(wǎng)鈣釋放通道的耦聯(lián)效率在心力衰竭中進(jìn)行性衰退,，且其關(guān)鍵原因是錨定兩分子所在膜結(jié)構(gòu)的JP2表達(dá)下降，有關(guān)成果被Nature Reviews Drug Discovery選為亮點,。在上述研究基礎(chǔ)上,，該實驗室繼續(xù)尋找心力衰竭過程中JP2表達(dá)量下降的原因，發(fā)現(xiàn)JP2基因的非編碼區(qū)有兩個miR-24結(jié)合位點,，且心力衰竭細(xì)胞中miR-24表達(dá)量顯著上升,。他們由此系統(tǒng)地證明，miR-24上調(diào)抑制了JP2的表達(dá),，從而導(dǎo)致心肌細(xì)胞興奮收縮耦聯(lián)的結(jié)構(gòu)重塑和效率下降,。
心血管領(lǐng)域大量研究證明，交感神經(jīng)遞質(zhì),、血管緊張素等導(dǎo)致心肌肥厚和心力衰竭的體液因子通過復(fù)雜的信號轉(zhuǎn)導(dǎo)啟動了NFAT等轉(zhuǎn)錄因子,，但這些轉(zhuǎn)錄因子的激活如何導(dǎo)致心臟收縮減弱一直未能闡明。由于miR-24位于NFAT調(diào)控的microRNA簇內(nèi),，上述發(fā)現(xiàn)第一次將上游信號轉(zhuǎn)導(dǎo)的途徑與下游收縮功能的減弱聯(lián)系起來,。Circulation Research配發(fā)的述評指出，該發(fā)現(xiàn)為未來探索心力衰竭的治療對策提供了新思路,。（生物谷Bioon.com）
doi: 10.1161/CIRCRESAHA.112.277418
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Mir-24 Regulates Junctophilin-2 Expression in Cardiomyocytes
Ming Xu*, Hao-Di Wu*, Rong-Chang Li*, Hai-Bo Zhang*, Meng Wang*, Jin Tao, Xin-Heng Feng, Yun-Bo Guo, Su-Fang Li, Shao-Ting Lai, Peng Zhou, Lin-Lin Li, Hua-Qian Yang, Guan-Zheng Luo, Yan Bai, Jianzhong J. Xi, Wei Gao, Qi-De Han, You-Yi Zhang, Xiu-Jie Wang, Xu Meng, Shi-Qiang Wang
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.
