MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling.
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MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. / Martins, Da Costa; Paula, A; Salic, Kanita; Gladka, Monika M; Armand, Anne-Sophie; Leptidis, Stefanos; Hansen, Arne; Hansen, Arne; Roo, Coenen-de; Christina, J; Bierhuizen, Marti F; van der Nagel, Roel; van Kuik, Joyce; de Weger, Roel; de Bruin, Alain; Eschenhagen, Thomas; Arbones, Maria L; Eschenhagen, Thomas; Windt, De; Leon, J.
In: NAT CELL BIOL, Vol. 12, No. 12, 12, 2010, p. 1220-1227.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling.
AU - Martins, Da Costa
AU - Paula, A
AU - Salic, Kanita
AU - Gladka, Monika M
AU - Armand, Anne-Sophie
AU - Leptidis, Stefanos
AU - Hansen, Arne
AU - Hansen, Arne
AU - Roo, Coenen-de
AU - Christina, J
AU - Bierhuizen, Marti F
AU - van der Nagel, Roel
AU - van Kuik, Joyce
AU - de Weger, Roel
AU - de Bruin, Alain
AU - Eschenhagen, Thomas
AU - Arbones, Maria L
AU - Eschenhagen, Thomas
AU - Windt, De
AU - Leon, J
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 12
SP - 1220
EP - 1227
JO - NAT CELL BIOL
JF - NAT CELL BIOL
SN - 1465-7392
IS - 12
M1 - 12
ER -
