1. Department of Medicine I,
2. Junior Research Group, Interdisziplinäres 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.

Correspondence to: Johann Bauersachs¹Stefan Engelhardt^3,14 Correspondence and requests for materials should be addressed to J.B. (Email: j.bauersachs@medizin.uni-wuerzburg.de) and S.E. (Email: stefan.engelhardt@tum.de).

Abstract

MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs^{1, 2}. Dysregulation of microRNAs by several mechanisms has been described in various disease states^{3, 4, 5} including cardiac disease^{6, 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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