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Nature:发现导致心力衰竭的遗传物质

来源:科技日报 2008-12-03 16:37

专题:Nature报道

德国科学家在《自然》(Nature)发表文章称,他们找到了一小片在心力衰竭中起关键作用的遗传物质,以及可阻止老鼠出现心力衰竭症状的一种化学物质。该发现表明,人们也许可通过微RNA靶向疗法来治疗该疾病。

该研究由德国维尔茨堡大学的斯蒂芬·恩格哈领导,研究人员分析了人和老鼠心脏样本中的几百种微RNA(核糖核酸)后,发现名为miR—21的微RNA是导致心力衰竭的一个关键原因。这些微RNA遗传碎片可对基因变成蛋白质的制造过程进行调整,研究人员发现,心力衰竭患者拥有的miR—21比普通人多3倍至4倍。

确定了这个基因碎片后,研究人员给老鼠喂食了一种名为antagomir的化学物质,该物质能使miR—21“失活”。研究人员发现,antagomir可抑制这些动物产生心力衰竭症状。同没有得到antagomir的动物相比,患有心力衰竭并接受antagomir治疗的动物的症状减轻了很多。

恩格哈说,通过antagomir的使用,研究人员既能阻止心脏病,也能治疗许多与心脏病相关的疾病。在这两种情况下,心脏功能和组织受到的损害都得到了一定程度的改善。

有关专家表示,这项新研究可能是微RNA治疗过程的一个里程碑,微RNA疗法是一类新的革新性治疗手段。该实验清楚地证明,微RNA靶向治疗对具有心力衰竭症状的动物具有疗效。

心脏长时间受到巨大的压力可能会导致心力衰竭症状。当人体出现这种症状时,心脏不能给身体组织供应充足的血流,由此可能引发感染、高血压和其他基因遗传疾病。全世界大约有2300万人正遭受此病的困扰,心力衰竭每年导致60万人死亡。

研究人员强调,RNA技术前景光明,已成为一个热点领域,正吸引着许多制药巨头纷纷“淘金”。今年4月份,葛兰素史克公司同Regulus医疗公司签署了价值6亿美元的合同,共同开发微RNA靶向治疗药物,以抢占该领域的新市场。微RNA靶向疗法主要针对由慢性炎症导致的疾病,比如风湿性关节炎、炎症性肠病等。(生物谷Bioon.com)

生物谷推荐原始出处:

Nature,doi:10.1038/nature07511,Thomas Thum,Stefan Engelhardt

MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts

Thomas Thum1,2,15, Carina Gross3,15, Jan Fiedler1,2, Thomas Fischer3, Stephan Kissler3, Markus Bussen5, Paolo Galuppo1, Steffen Just6, Wolfgang Rottbauer6, Stefan Frantz1, Mirco Castoldi7,8, Jürgen Soutschek9, Victor Koteliansky10, Andreas Rosenwald4, M. Albert Basson11, Jonathan D. Licht12, John T. R. Pena13, Sara H. Rouhanifard13, Martina U. Muckenthaler7,8, Thomas Tuschl13, Gail R. Martin5, Johann Bauersachs1 & Stefan Engelhardt3,14

1 Department of Medicine I,
2 Junior Research Group, Interdisziplin?res Zentrum für Klinische Forschung (IZKF)
3 Rudolf Virchow Center, Deutsche Forschungsgemeinschaft (DFG) Research Center for Experimental Biomedicine,
4 Institute of Pathology, University of Wuerzburg, 97080 Wuerzburg, Germany
5 Department of Anatomy, University of California, San Francisco, California 94158, USA
6 Department of Internal Medicine III,
7 Department of Pediatric Hematology, Oncology and Immunology
8 Molecular Medicine Partnership Unit, University of Heidelberg, 69120 Heidelberg, Germany
9 Regulus Therapeutics, Carlsbad, California 92008, USA
10 Alnylam Pharmaceuticals, Cambridge, Massachusetts 02142, USA
11 Department of Craniofacial Development, King's College, London SE1 9RT, UK
12 Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA
13 Laboratory of RNA Molecular Biology, Rockefeller University, New York, New York 10065, USA
14 Institute of Pharmacology and Toxicology, Technische Universitaet Muenchen (TUM), 80802 Muenchen, Germany.
15 These authors contributed equally to this work.

MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs1, 2. Dysregulation of microRNAs by several mechanisms has been described in various disease states3, 4, 5 including cardiac disease6, 7, 8, 9, 10. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK–MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK–MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK–MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.

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