cAMP is a powerful second messenger whose known general effector is protein kinase A (PKA). : from 2.4 ± 0.6 to 6.9 ± 1.5, P < 0.01) while reducing their amplitude (F/F 0 : 1.8 ± 0.02 versus 1.6 ± 0.01, P < 0.001) in a Ca 2+ /calmodulin kinase II (CaMKII)-dependent and PKA-independent manner. Accordingly, we found that Epac increased RyR phosphorylation at the CaMKII site. Altogether, our data reveal a new signalling pathway by which cAMP governs Ca 2+ release and signalling in cardiac myocytes.

Abstract-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 ␤-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 2ϩ /calmodulin-dependent protein kinase II. Importantly, we find that in response to ␤-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 ␤-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 ␤-adrenergic receptor in a protein kinase A-independent fashion and may, therefore, represent a novel therapeutic target for the treatment of cardiac disorders. Key Words: G protein-coupled receptor Ⅲ small G protein Ⅲ cardiac hypertrophy T he ␤-adrenergic receptor (␤-AR) is a prototypical member of the G protein-coupled receptor superfamily and plays a central role in sympathetic regulation of cardiac function. 1 Although acute stimulation of ␤-ARs has beneficial effects on heart function, accumulating evidence suggests that their chronic activation causes progressive cardiac dysfunction, cell loss, and cardiac chamber remodeling in human. 2,3 Consistent with this notion, it has been demonstrated that chronic stimulation of ␤-ARs causes hypertrophy in cardiac myocytes. 4 Adult myocyte hypertrophy is the compensatory response of the heart to stress and is characterized by nonmitotic growth, addition of new sarcomeres, fetal gene expression, and specific changes in ion channel properties. 5 Maladaptive cardiac hypertrophy can progress to heart failure (HF), a leading cause of morbidity and mortality in industrialized countries. Thus, understanding the signaling mechanisms that mediate the growth of adult cardiac myocytes by ␤-AR stimulation may lead to better treatment for patients with HF.Although cAMP is among the most well-known signaling molecules produced by ␤-AR stimulation, its mechanism of action in cardiac growth is not ...