title: 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 length. Increasing evidence implicates miRs in myocardial disease processes. 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.
authors.affiliation: Hubrecht Institute, Royal Netherlands Academy of Sciences, PO Box 85164, Utrecht, The Netherlands.
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.forename: Kanita
authors.initials: K
authors.lastname: Salic
authors.forename: Monika M
authors.initials: MM
authors.lastname: Gladka
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Armand
authors.forename: Stefanos
authors.initials: S
authors.lastname: Leptidis
authors.forename: Hamid
authors.initials: H
authors.lastname: el Azzouzi
authors.forename: Arne
authors.initials: A
authors.lastname: Hansen
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Coenen-de Roo
authors.forename: Marti F
authors.initials: MF
authors.lastname: Bierhuizen
authors.forename: Roel
authors.initials: R
authors.lastname: van der Nagel
authors.forename: Joyce
authors.initials: J
authors.lastname: van Kuik
authors.forename: Roel
authors.initials: R
authors.lastname: de Weger
authors.forename: Alain
authors.initials: A
authors.lastname: de Bruin
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Condorelli
authors.forename: Maria L
authors.initials: ML
authors.lastname: Arbones
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D006333:Heart Failure / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D000097603:Dyrk Kinases
chemical_list: D019703:Calcineurin; D035683:MicroRNAs; D050778:NFATC Transcription Factors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C534780:Mirn199 microRNA, mouse; C531408:mirn199 microRNA, human