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

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.

• Authors: Cornelia Grebe, Theda-Maria Klingebiel, Simon Philipp Grau, Karl Toischer, Michael Didié, Claudius Jacobshagen, Christian Dullin, Gerd Hasenfuss, Tim Seidler
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 90 Issue 3 Pg. 521-8 (Jun 01 2011) ISSN: 1755-3245 [Electronic] England
• PMID: 21273244 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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