title: Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo.
abstract: OBJECTIVE
  The calcineurin and nuclear factor of activated T cells (NFAT) pathway can mediate pro-hypertrophic signalling in the heart. Recently, it has been shown that dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) phosphorylates NFAT, which limits calcineurin/NFAT signal transduction in T cells and hypertrophy in cultured cardiomyocytes. The hypothesis tested in this study was that DYRK1A prevents calcineurin/NFAT-mediated cardiac hypertrophy in vivo.
  
  
  RESULTS
  In cultured rat cardiomyocytes, adenovirus-mediated overexpression of DYRK1A antagonized calcineurin-mediated nuclear NFAT translocation and the phenylephrine-induced hypertrophic growth response. To test the ability of DYRK1A to reduce hypertrophic cardiac growth in vivo, we created tetracycline-repressible Dyrk1a transgenic mice to avoid the cardiac developmental defects associated with embryonic DYRK1A expression. However, in the mouse model, histological determination of myocyte diameter, heart weight/body weight ratio, and echocardiographic measurements revealed that myocardial expression of DYRK1A failed to reduce hypertrophy induced via aortic banding or co-expression of calcineurin. This discrepancy is explained, at least in part, by insufficient long-term inhibition of NFAT and the activation of DYRK1A-resistant maladaptive genes in vivo.
  
  
  CONCLUSIONS
  Isolated augmentation of DYRK1A can be compensated for in vivo, and this may significantly limit anti-hypertrophic interventions aimed at enhancing DYRK1A activity.
authors.affiliation: Department of Cardiology and Pulmonology, Georg-August-University, Robert-Koch Str. 40, 37075 Göttingen, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Grebe
authors.forename: Theda-Maria
authors.initials: TM
authors.lastname: Klingebiel
authors.forename: Simon Philipp
authors.initials: SP
authors.lastname: Grau
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Michael
authors.initials: M
authors.lastname: Didié
authors.forename: Claudius
authors.initials: C
authors.lastname: Jacobshagen
authors.forename: Christian
authors.initials: C
authors.lastname: Dullin
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Tim
authors.initials: T
authors.lastname: Seidler
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097603:Dyrk Kinases
chemical_list: D019703:Calcineurin; D050778:NFATC Transcription Factors; D010656:Phenylephrine; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D000097603:Dyrk Kinases