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MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling

Abstract

MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length1,2. Increasing evidence implicates miRs in myocardial disease processes3,4,5,6,7,8,9,10,11. Here we show that miR-199b is a direct calcineurin/NFAT target gene that increases in expression in mouse and human heart failure, and targets the nuclear NFAT kinase dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1a (Dyrk1a), constituting a pathogenic feed forward mechanism that affects calcineurin-responsive gene expression. Mutant mice overexpressing miR-199b, or haploinsufficient for Dyrk1a, are sensitized to calcineurin/NFAT signalling or pressure overload and show stress-induced cardiomegaly through reduced Dyrk1a expression. In vivo inhibition of miR-199b by a specific antagomir normalized Dyrk1a expression, reduced nuclear NFAT activity and caused marked inhibition and even reversal of hypertrophy and fibrosis in mouse models of heart failure. Our results reveal that microRNAs affect cardiac cellular signalling and gene expression, and implicate miR-199b as a therapeutic target in heart failure.

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Figure 1: Increased expression of miR-199b in cardiac disease.
Figure 2: miR-199b promotes hypertrophy and targets Dyrk1a in cardiomyocytes.
Figure 3: miR-199b overexpression sensitizes the myocardium to pathological cardiac hypertrophy.
Figure 4: Dyrk1a haploinsufficiency exacerbates and miR-199b silencing prevents cardiac remodeling.
Figure 5: miR-199b silencing prevents and reverses cardiac remodelling and dysfunction.

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Acknowledgements

We gratefully acknowledge T. Seidler and J. Molkentin for adenoviruses; R. Hesdahl and D. Bogaert for logistical and technical support; and members of the De Windt laboratory for technical support and helpful discussions. P.D.C.M. was supported by a Heart Failure Association Research Fellowship from the European Society of Cardiology. L.D.W. was supported by grants 912-04-054, 912-04-017 and a VIDI award 917-863-72 from the Netherlands Organization for Health Research and Development and the Netherlands Heart Foundation program grant NHS2007B167. G.C. and L.D.W were supported by the Fondation Leducq Transatlantic Network of Excellence program 08-CVD-03.

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P.D.C.M, K.S., M.G., A.S., S.L., H.A., A.H., M.B., R.N., J.K and L.D.W. performed the experiments; P.D.C.M, K.S., M.G., A.S., C.C., M.A., T.E. and L.D.W. analysed the data; P.D.C.M., K.S. and L.D.W designed the study; P.D.C.M, K.S. and L.D.W. wrote the manuscript; P.D.C.M. and K.S. contributed equally as joint first authors.

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Correspondence to Leon J. De Windt.

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da Costa Martins, P., Salic, K., Gladka, M. et al. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nat Cell Biol 12, 1220–1227 (2010). https://doi.org/10.1038/ncb2126

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