cAMP-binding protein Epac induces cardiomyocyte hypertrophy.
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.
Morel
Eric
E
Cardiologie Cellulaire et Moléculaire, Inserm U-446, IFR-75, Faculté de Pharmacie, Université Paris XI, 5 Rue JB Clément, 92296 Chātenay Malabry, France.
Marcantoni
Andrea
A
Gastineau
Monique
M
Birkedal
Rikke
R
Rochais
Francesca
F
Garnier
Anne
A
Lompré
Anne-Marie
AM
Vandecasteele
Grégoire
G
Lezoualc'h
Frank
F
D021581:Active Transport, Cell Nucleus; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D019703:Calcineurin / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D016762:Genes, fos; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology; D020744:rac GTP-Binding Proteins / Q000378:metabolism
C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D050778:NFATC Transcription Factors; D013873:Thionucleotides; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin; D020744:rac GTP-Binding Proteins; D002118:Calcium