5月31从哈尔滨医科大学了解到，我国学者首次捕捉到导致心律失常新靶点———一种被称为“miRNA”的非编码遗传物质，并从分子生物学角度揭示了其致病机理，结果证实miRNA的失衡，正是引起致死性心律失常发生的重要“元凶”。
由哈尔滨医科大学药理学家杨宝峰教授领衔完成的这一重大原创性成果，刊登于今年4月出版的英文期刊《自然医学》上，国际著名心脏生理学家MarkE.Anderson和PeterJ.Mohler评价说：“杨的发现有力地证明了miRNA是心律失常电重构和心律失常发生的重要调节物质，抑制miRNA可明显降低心梗患者心源性猝死的发生率，这为心源性猝死的防治带来了新希望。”
心力衰竭与心律失常是导致心脏病人死亡的主要原因。我国心力衰竭患者近千万，心力衰竭确诊后4年死亡率高达50%，每年因恶性心律失常猝死者近百万。由于遗传背景、生活环境和疾病谱的差异，一些对西方人群有效的防治措施并不完全适合于国人，同时，目前临床主要使用的四大类抗心律失常药物均疗效不佳。
miRNA为大约22个核苷酸所组成的非编码遗传物质，目前人们对它的认识仅停留在“组织特异性、阶段依赖性表达及进化保守”层面上，未能从根本上揭开其神秘的“面纱”。杨宝峰课题组发现，与正常人类心脏相比，冠心病患者miRNA表达可增高2.8倍。课题组通过细胞转染技术将miRNA应用于心律失常模型大鼠体内进行试验，结果发现miRNA是心律失常的致病因子，并且加重心律失常。研究还发现，miRNA主要通过调节体内的某些蛋白质的变化，而导致心律失常的发生。(生物谷援引科技日报)
原始出处:
Letter abstract
Nature Medicine 13, 486 - 491 (2007)
Published online: 1 April 2007 | doi:10.1038/nm1569
The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2
Baofeng Yang1,2,5, Huixian Lin2,3,4,5, Jiening Xiao2,3,4,5, Yanjie Lu1,2, Xiaobin Luo2,3,4, Baoxin Li1, Ying Zhang1, Chaoqian Xu1, Yunlong Bai1, Huizhen Wang1,3, Guohao Chen1 & Zhiguo Wang2,3,4
Abstract
MicroRNAs (miRNAs) are endogenous noncoding RNAs, about 22 nucleotides in length, that mediate post-transcriptional gene silencing by annealing to inexactly complementary sequences in the 3'-untranslated regions of target mRNAs1, 2, 3. Our current understanding of the functions of miRNAs relies mainly on their tissue-specific or developmental stage-dependent expression and their evolutionary conservation, and therefore is primarily limited to their involvement in developmental regulation and oncogenesis2. Of more than 300 miRNAs that have been identified, miR-1 and miR-133 are considered to be muscle specific4, 5, 6. Here we show that miR-1 is overexpressed in individuals with coronary artery disease, and that when overexpressed in normal or infarcted rat hearts, it exacerbates arrhythmogenesis. Elimination of miR-1 by an antisense inhibitor in infarcted rat hearts relieved arrhythmogenesis. miR-1 overexpression slowed conduction and depolarized the cytoplasmic membrane by post-transcriptionally repressing KCNJ2 (which encodes the K+ channel subunit Kir2.1) and GJA1 (which encodes connexin 43), and this likely accounts at least in part for its arrhythmogenic potential. Thus, miR-1 may have important pathophysiological functions in the heart, and is a potential antiarrhythmic target.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang 150086, China.
Institute of Cardiovascular Research, Harbin Medical University, Harbin, Heilongjiang 150086, China.
Research Center, Montreal Heart Institute, 5000 Belanger East, Montreal PQ H1T 1C8, Canada.
Department of Medicine, University of Montreal, Montreal PQ H3C 3J7, Canada.
These authors contributed equally to this work.
Correspondence to: Zhiguo Wang2,3,4 e-mail: wz.email@gmail.com
Correspondence to: Baofeng Yang1,2,5 e-mail: yangbf@ems.hrbmu.edu.cn
