DYRK1A is a novel negative regulator of cardiomyocyte hypertrophy.

Abstract

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.

• Authors: Christian Kuhn, Derk Frank, Rainer Will, Christoph Jaschinski, Robert Frauen, Hugo A Katus, Norbert Frey
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 25 Pg. 17320-17327 (Jun 19 2009) ISSN: 1083-351X [Electronic] United States
• PMID: 19372220 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin-1
• MicroRNAs
• NFATC Transcription Factors
• Protein Kinase Inhibitors
• RNA, Messenger
• Recombinant Proteins
• Phenylephrine
• Harmine
• Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• Calcineurin

Topics

• Animals
• Base Sequence
• Calcineurin (metabolism, pharmacology)
• Calcium Signaling
• Cardiomegaly (enzymology, etiology, pathology)
• Cell Enlargement (drug effects)
• Cells, Cultured
• Endothelin-1 (pharmacology)
• Gene Expression
• Harmine (pharmacology)
• MicroRNAs (genetics)
• Models, Cardiovascular
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• NFATC Transcription Factors (metabolism)
• Phenylephrine (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, physiology)
• Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, physiology)
• RNA, Messenger (genetics, metabolism)
• Rats
• Recombinant Proteins (genetics, metabolism)
• Dyrk Kinases