西亞試劑優(yōu)勢供應上萬種化學試劑產品，歡迎各位新老客戶咨詢、選購！
中國
聯(lián)系我們
聯(lián)系方式：400-990-3999 / 郵箱：sales@xiyashiji.com
西亞試劑 —— 品質可靠，值得信賴
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.
