BEC and br Epac in cardiovascular pathophysiology
Epac in cardiovascular pathophysiology Epac orchestrates signaling actors that regulate fundamental cellular functions and general biological effects. However, some important gaps still remain in the knowledge of the physiopathological role of Epac in the heart. So far, Epac has been implicated in several cardiac pathologies such as cardiac hypertrophy and arrhythmia, although it may have effects on other pathological responses such as apoptosis  and fibrosis , , .
Concluding remarks and future directions All these evidences point to Epac as a new important signaling molecule in the heart. By rapidly inducing Ca mobilization and activating ET coupling, Epac induces latter on a positive inotropic effect, together with cellular hypertrophy. Therefore, Epac could be an essential player in the cellular cardiac remodeling under chronic adrenergic stimulation, allowing the heart to adapt to stress conditions, but with the counterpart of arrhythmogenic side effects. Nevertheless, the studies up to date are limited because of the limited available tools. Data rely on pharmacological interventions to activate Epac and no specific inhibitor is still available. Although at the cellular level, up and down regulations of Epac have been used, studies in an integrated model as transgenic mice will be valuable to discriminate the in vivo physiologic and pathologic roles of Epac. Taken together, recent data demonstrate that the BEC and nucleotide exchange factor Epac1 contributes to the hypertrophic effect of β-AR in a PKA independent fashion and through Ca homeostasis in an ET coupling way. Epac may therefore represent a novel therapeutic target for the treatment of cardiac disorders. However, the cellular processes and signaling pathways of this GEF are intriguingly more and more complex. Moreover, Epac action depends on the “when, where, and how” this protein is activated by distinct cAMP pools and may therefore constitute an adaptive mechanism of cell survival.
Introduction cAMP is a universal second messenger that plays a central role in the regulation of cardiac contractility. In the last years, it has become recognized that along with the cAMP effector protein kinase A (PKA), the exchange protein directly activated by cAMP (Epac) participates in many cAMP-controlled processes of heart function. Among them, activation of Epac has been involved in the regulation of Ca homeostasis in cardiac myocytes, Ca myofilament sensitivity, gap junction formation, arrhythmogenesis, apoptosis, autophagy, hypertrophy, vascular integrity and cardiac fibrosis , . The Epac protein family is composed of Epac1 and Epac2, which act as guanine-nucleotide exchange factors for the small G proteins Rap1 and Rap2, in a PKA-independent manner. In mouse and human hearts, Epac1 is the most abundant isoform ,  and its expression is developmentally regulated, with the Epac1/Epac2 mRNA ratio decreasing in adulthood . Several studies in isolated cardiac myocytes have shown that stimulation of Epac by the selective activator, 8-(4-chloro-phenylthio)-2′-O-methyladenosine-3′, 5′-cyclic monophosphate (8-CPT), increased the activity of the Ca and calmodulin-dependent protein kinase II (CaMKII) and the phosphorylation of two sarcoplasmic reticulum (SR) targets, the Ca release channel (RyR2) and the Ca pump (SERCA2a) regulator, phospholamban (PLN) , , , , . Moreover, at the level of the myofibrils, 8-CPT enhanced the CaMKII-dependent phosphorylation of myosin-binding protein C (MyBPC) and troponin I (TnI) . Even though CaMKII appears as a clear downstream signal of Epac, the pathway that leads to its activation is still debated. The Epac-mediated effects have been shown to require the presence of ε isoform of phospholipase C (PLCε) ,  and the resultant increase in cytosolic Ca triggered by IP3 as well as the diacylglycerol-activated PKCε, have been implicated in the stimulation of CaMKII under different experimental conditions (5, 7, 10). Additionally, it has recently been reported a nitric oxide synthase and phosphoinositide 3-kinase dependent activation of CaMKII during Epac stimulation .