Enhanced expression of DYRK1A in cardiomyocytes inhibits acute NFAT activation but does not prevent hypertrophy in vivo

Cardiovasc Res. 2011 Jun 1;90(3):521-8. doi: 10.1093/cvr/cvr023. Epub 2011 Jan 27.

Abstract

Aims: 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.

Methods and 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.

Conclusion: Isolated augmentation of DYRK1A can be compensated for in vivo, and this may significantly limit anti-hypertrophic interventions aimed at enhancing DYRK1A activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin / metabolism
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism*
  • Cardiomegaly / pathology
  • Cardiomegaly / prevention & control
  • Cells, Cultured
  • Dyrk Kinases
  • Female
  • Gene Knockdown Techniques
  • Male
  • Mice
  • Mice, Transgenic
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology*
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Phenylephrine / pharmacology
  • Pregnancy
  • Protein Serine-Threonine Kinases / antagonists & inhibitors
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / metabolism*
  • Rats
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction

Substances

  • NFATC Transcription Factors
  • Recombinant Proteins
  • Phenylephrine
  • Protein-Tyrosine Kinases
  • Protein Serine-Threonine Kinases
  • Calcineurin