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


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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Figure 1: Deregulation of miR-21 expression in cardiac disease.
Figure 2: miR-21 promotes ERK–MAP-kinase-mediated cell survival in cardiac fibroblasts.
Figure 3: miR-21 derepresses ERK signalling and enhances fibroblast survival by inhibiting SPRY1 expression.
Figure 4: Efficacy of miR-21 silencing in preventing and treating cardiac disease.


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We thank N. Hemmrich, U. Keller, J. Schittl, C. Dienesch, S. Thum, A. Leupold, M. Kümmel, S. Schraut, A. Lauer, S. Marquart, E. Leich and A. Horn for technical assistance. We acknowledge the contribution of V. Benes and S. Schmidt (miChip microarray Platform, EMBL), D. Fraccarollo and K. Hu (in vivo studies), S. Leierseder and X. Loyer (primary fibroblast preparation), C. Sohn-Lee (in situ hybridization experiments) and M. Manoharan, R. Braich and B. Bhat (antagomir oligonucleotides). We also thank L. Field, T. Brand and M. Gessler for discussions. This work was supported in part by grants from the IZKF (E-31 to T. Thum), the Deutsche Forschungsgemeinschaft (DFG TH903/7-1 to T. Thum and J.B.), the Rudolf Virchow Center/DFG Research Center for Experimental Biomedicine (S.E., S.K.), the Bavarian Ministry of Technology, ProCorde and Sanofi-Aventis (S.E.), and the US NIH (R01 CA78711 to G.R.M.). M.C. is supported by an Excellence Fellowship of The Medical Faculty of the University of Heidelberg, M.U.M. by a Cancer Research Net grant (BMBF (NGFN) 201GS0450), and M.B. by the Leopoldina Academy (BMBF-LPD 9901/8-141).

Author Contributions T. Thum, C.G., J.F., T.F., S.K., M.B., P.G., S.J., M.C. and S.E. performed experiments. M.A.B and J.D.L. provided the Spry/LacZ mouse line. J.T.R.P., S.H.R. and T. Tuschl contributed the in situ hybridization experiments. T. Thum, C.G., J.F., W.R., S.F., J.S., V.K., A.R., M.M., G.R.M., J.B. and S.E. analysed data. T. Thum, J.B. and S.E. designed the study. T. Thum, G.R.M., J.B. and S.E. wrote the manuscript. J.B. and S.E. contributed equally as joint senior authors to the study.

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Correspondence to Johann Bauersachs or Stefan Engelhardt.

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T. Thum, C.G., J.B. and S.E. have submitted a patent application on the use of microRNAs in heart disease.

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Thum, T., Gross, C., Fiedler, J. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

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