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

Paula A. da Costa Martins, Kanita Salic, Monika M. Gladka, Anne-Sophie Armand, Stefanos Leptidis, Hamid el Azzouzit, Arne Hansen, Christina J. Coenen-de Roo, Marti F. A. Bierhuizen, Roel van der Nagel, Joyce van Kuik, Roel A. de Weger, Alain de Bruin, Gianluigi Condorelli, Maria L. Arbones, Thomas Eschenhagen, Leon J. De Windt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

210 Citations (Web of Science)

Abstract

MicroRNAs (miRs) are a class of single-stranded, non-coding RNAs of about 22 nucleotides in length(1,2). Increasing evidence implicates miRs in myocardial disease processes(3-11). 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.
Original languageEnglish
Pages (from-to)1220-U231
JournalNature Cell Biology
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2010

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