Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy.
Cardiac hypertrophy is promoted by adrenergic overactivation and can progress to heart failure, a leading cause of mortality worldwide. Although cAMP is among the most well-known signaling molecules produced by beta-adrenergic receptor stimulation, its mechanism of action in cardiac hypertrophy is not fully understood. The identification of Epac (exchange protein directly activated by cAMP) proteins as novel sensors for cAMP has broken the dogma surrounding cAMP and protein kinase A. However, their role and regulation in the mature heart remain to be defined. Here, we show that cardiac hypertrophy induced by thoracic aortic constriction increases Epac1 expression in rat myocardium. Adult ventricular myocytes isolated from banded animals display an exaggerated cellular growth in response to Epac activation. At the molecular level, Epac1 hypertrophic effects are independent of its classic effector, Rap1, but rather involve the small GTPase Ras, the phosphatase calcineurin, and Ca(2+)/calmodulin-dependent protein kinase II. Importantly, we find that in response to beta-adrenergic receptor stimulation, Epac1 activates Ras and induces adult cardiomyocyte hypertrophy in a cAMP-dependent but protein kinase A-independent manner. Knockdown of Epac1 strongly reduces beta-adrenergic receptor-induced hypertrophic program. Finally, we report for the first time that Epac1 is mainly expressed in human heart as compared with Epac2 isoform and is increased in heart failure. Taken together, our data demonstrate that the guanine nucleotide exchange factor Epac1 contributes to the hypertrophic effect of beta-adrenergic receptor in a protein kinase A-independent fashion and may, therefore, represent a novel therapeutic target for the treatment of cardiac disorders.
Métrich
Mélanie
M
Inserm, U769, Signalisation et Physiopathologie Cardiaque, Châtenay-Malabry, F-92296, France.
Lucas
Alexandre
A
Gastineau
Monique
M
Samuel
Jane-Lise
JL
Heymes
Christophe
C
Morel
Eric
E
Lezoualc'h
Frank
F
D000818:Animals; D019703:Calcineurin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006332:Cardiomegaly / Q000209:etiology*; D017868:Cyclic AMP-Dependent Protein Kinases; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis* / Q000502:physiology*; D006801:Humans; D006984:Hypertrophy / Q000209:etiology*; D032383:Myocytes, Cardiac / Q000473:pathology*; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018631:ras Proteins
D020662:Guanine Nucleotide Exchange Factors; C116122:RAPGEF3 protein, human; C526973:Rapgef3 protein, rat; D011943:Receptors, Adrenergic, beta; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin; D018631:ras Proteins