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

Abstract

Calcineurin signalling or pressure overload is shown to lead to cardiac hypertrophy through NFAT-mediated increase in miR-199. miR-199 inhibits the Dyrk1a kinase, which leads to further activation of NFAT. Inhibition of miR-199 reverses hypertrophy and fibrosis in mouse models of cardiac failure. 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.

Cite this article

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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