DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy.
Activation of the phosphatase calcineurin and its downstream targets, transcription factors of the NFAT family, results in cardiomyocyte hypertrophy. Recently, it has been shown that the dual specificity tyrosine (Y) phosphorylation-regulated kinase 1A (DYRK1A) is able to antagonize calcineurin signaling by directly phosphorylating NFATs. We thus hypothesized that DYRK1A might modulate the hypertrophic response of cardiomyocytes. In a model of phenylephrine-induced hypertrophy, adenovirus-mediated overexpression of DYKR1A completely abrogated the hypertrophic response and significantly reduced the expression of the natriuretic peptides ANF and BNP. Furthermore, DYRK1A blunted cardiomyocyte hypertrophy induced by overexpression of constitutively active calcineurin and attenuated the induction of the hypertrophic gene program. Conversely, knockdown of DYRK1A, utilizing adenoviruses encoding for a specific synthetic miRNA, resulted in an increase in cell surface area accompanied by up-regulation of ANF- mRNA. Similarly, treatment of cardiomyocytes with harmine, a specific inhibitor of DYRK1A, revealed cardiomyocyte hypertrophy on morphological and molecular level. Moreover, constitutively active calcineurin led to robust induction of an NFAT-dependent luciferase reporter, whereas DYRK1A attenuated calcineurin-induced reporter activation in cardiomyocytes. Conversely, both knockdown and pharmacological inhibition of DYRK1A significantly augmented the effect of calcineurin in this assay. In summary, we identified DYRK1A as a novel negative regulator of cardiomyocyte hypertrophy. Mechanistically, this effect appears to be mediated via inhibition of NFAT transcription factors.
From the Department of Internal Medicine III, Cardiology, Angiology, and Pneumology, University Hospital of Heidelberg, Heidelberg 69120; Department of Cardiology and Angiology, University of Kiel, Kiel 24105, Germany.
Christian
C
Kuhn
From the Department of Internal Medicine III, Cardiology, Angiology, and Pneumology, University Hospital of Heidelberg, Heidelberg 69120.
Derk
D
Frank
From the Department of Internal Medicine III, Cardiology, Angiology, and Pneumology, University Hospital of Heidelberg, Heidelberg 69120.
Rainer
R
Will
From the Department of Internal Medicine III, Cardiology, Angiology, and Pneumology, University Hospital of Heidelberg, Heidelberg 69120.
Christoph
C
Jaschinski
From the Department of Internal Medicine III, Cardiology, Angiology, and Pneumology, University Hospital of Heidelberg, Heidelberg 69120.
Robert
R
Frauen
From the Department of Internal Medicine III, Cardiology, Angiology, and Pneumology, University Hospital of Heidelberg, Heidelberg 69120.
Hugo A
HA
Katus
Department of Cardiology and Angiology, University of Kiel, Kiel 24105, Germany. Electronic address: norbert.frey@uk-sh.de.
Norbert
N
Frey
D000818:Animals; D001483:Base Sequence; D019703:Calcineurin / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D049108:Cell Enlargement / Q000187:drug effects; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D015870:Gene Expression; D006247:Harmine / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
D019703:Calcineurin; D019332:Endothelin-1; D006247:Harmine; D035683:MicroRNAs; D050778:NFATC Transcription Factors; D010656:Phenylephrine; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000097603:Dyrk Kinases