Published online before print November 3, 2005, doi: 10.1161/01.RES.0000194325.31359.86
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© 2005 American Heart Association, Inc.
Cellular Biology |
cAMP-Binding Protein Epac Induces Cardiomyocyte Hypertrophy
From the Cardiologie Cellulaire et Moléculaire, Inserm U-446, IFR-75, Faculté de Pharmacie, Université Paris XI, 5 Rue JB Clément, 92296 Ch
tenay Malabry, France
Correspondence to Frank Lezoualc’h, Cardiologie Cellulaire et Moléculaire, Inserm U-446, IFR-75, Faculté de Pharmacie, Université Paris XI, 5 Rue JB Clément, 92296 Chtenay Malabry, France. E-mail Frank.Lezoualch{at}cep.u-psud.fr
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.
Key Words: cAMP • guanine nucleotide exchange factor • small G protein • transcription factor
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