cAMP-binding protein Epac induces cardiomyocyte hypertrophy.

Abstract

cAMP is one of the most important second messenger in the heart. The discovery of Epac as a guanine exchange factor (GEF), which is directly activated by cAMP, raises the question of the role of this protein in cardiac cells. Here we show that Epac activation leads to morphological changes and induces expression of cardiac hypertrophic markers. This process is associated with a Ca2+-dependent activation of the small GTPase, Rac. In addition, we found that Epac activates a prohypertrophic signaling pathway, which involves the Ca2+ sensitive phosphatase, calcineurin, and its primary downstream effector, NFAT. Rac is involved in Epac-induced NFAT dependent cardiomyocyte hypertrophy. Blockade of either calcineurin or Rac activity blunts the hypertrophic response elicited by Epac indicating these signaling molecules coordinately regulate cardiac gene expression and cellular growth. Our results thus open new insights into the signaling pathways by which cAMP may mediate its biological effects and identify Epac as a new positive regulator of cardiac growth.

• Authors: Eric Morel, Andrea Marcantoni, Monique Gastineau, Rikke Birkedal, Francesca Rochais, Anne Garnier, Anne-Marie Lompré, Grégoire Vandecasteele, Frank Lezoualc'h
• Journal: Circulation research (Circ Res) Vol. 97 Issue 12 Pg. 1296-304 (Dec 09 2005) ISSN: 1524-4571 [Electronic] United States
• PMID: 16269655 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Epac protein, mouse
• Guanine Nucleotide Exchange Factors
• NFATC Transcription Factors
• Thionucleotides
• 8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
• Atrial Natriuretic Factor
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Calcineurin
• rac GTP-Binding Proteins
• Calcium

Topics

• Active Transport, Cell Nucleus
• Adenoviridae (genetics)
• Animals
• Atrial Natriuretic Factor (genetics)
• Calcineurin (physiology)
• Calcium (metabolism)
• Cardiomegaly (etiology)
• Cyclic AMP (analogs & derivatives, pharmacology)
• Cyclic AMP-Dependent Protein Kinases (physiology)
• Genes, fos
• Guanine Nucleotide Exchange Factors (physiology)
• NFATC Transcription Factors (metabolism)
• Promoter Regions, Genetic
• Rats
• Signal Transduction
• Thionucleotides (pharmacology)
• rac GTP-Binding Proteins (metabolism)