5月31從哈爾濱醫(yī)科大學(xué)了解到,，我國(guó)學(xué)者首次捕捉到導(dǎo)致心律失常新靶點(diǎn)———一種被稱為“miRNA”的非編碼遺傳物質(zhì),，并從分子生物學(xué)角度揭示了其致病機(jī)理,，結(jié)果證實(shí)miRNA的失衡,，正是引起致死性心律失常發(fā)生的重要“元兇”。
由哈爾濱醫(yī)科大學(xué)藥理學(xué)家楊寶峰教授領(lǐng)銜完成的這一重大原創(chuàng)性成果,，刊登于今年4月出版的英文期刊《自然醫(yī)學(xué)》上,，國(guó)際著名心臟生理學(xué)家MarkE.Anderson和PeterJ.Mohler評(píng)價(jià)說(shuō)：“楊的發(fā)現(xiàn)有力地證明了miRNA是心律失常電重構(gòu)和心律失常發(fā)生的重要調(diào)節(jié)物質(zhì)，抑制miRNA可明顯降低心?；颊咝脑葱遭赖陌l(fā)生率,，這為心源性猝死的防治帶來(lái)了新希望。”
心力衰竭與心律失常是導(dǎo)致心臟病人死亡的主要原因。我國(guó)心力衰竭患者近千萬(wàn),，心力衰竭確診后4年死亡率高達(dá)50%,，每年因惡性心律失常猝死者近百萬(wàn)。由于遺傳背景,、生活環(huán)境和疾病譜的差異,，一些對(duì)西方人群有效的防治措施并不完全適合于國(guó)人，同時(shí),，目前臨床主要使用的四大類抗心律失常藥物均療效不佳,。
miRNA為大約22個(gè)核苷酸所組成的非編碼遺傳物質(zhì)，目前人們對(duì)它的認(rèn)識(shí)僅停留在“組織特異性,、階段依賴性表達(dá)及進(jìn)化保守”層面上,，未能從根本上揭開(kāi)其神秘的“面紗”。楊寶峰課題組發(fā)現(xiàn),，與正常人類心臟相比,，冠心病患者miRNA表達(dá)可增高2.8倍。課題組通過(guò)細(xì)胞轉(zhuǎn)染技術(shù)將miRNA應(yīng)用于心律失常模型大鼠體內(nèi)進(jìn)行試驗(yàn),，結(jié)果發(fā)現(xiàn)miRNA是心律失常的致病因子,，并且加重心律失常。研究還發(fā)現(xiàn),，miRNA主要通過(guò)調(diào)節(jié)體內(nèi)的某些蛋白質(zhì)的變化,，而導(dǎo)致心律失常的發(fā)生。(生物谷援引科技日?qǐng)?bào))
原始出處:
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: [email protected]
Correspondence to: Baofeng Yang1,2,5 e-mail: [email protected]
