Résumé
Exchange proteins directly activated by cAMP (EPAC), EPAC1 and EPAC2 are involved in electrophysiological modulation in ventricular cardiomyocytes. Their putative contribution in supra-ventricular arrhythmogenic processes have been suggested in animal models. However, little is known about the exact electrophysiological remodeling and the underlying signaling pathway regulated by EPAC in human atrial cardiomyocyte. Action potentials (AP) and K+ currents (IK) were recorded with the patch clamp technique in enzymatically freshly isolated human atrial cardiomyocytes. Acute EPAC activation with the EPAC agonist, 8-CPT-AM (10 μM) lengthened AP by inhibition of the repolarizing K+ current in myocytes obtained from sinus rhythm (SR) patients. The selective EPAC1 pharmacological blocker AM-001 (20 μM) or the EPAC2 inhibitor ESI-05 (25 μM) prevented the effect of 8-CPT-AM on AP and IK indicating that both EPAC isoforms participate in electrophysiological regulation. Mechanistically, the effects of EPAC1 and EPAC2 proteins on the inhibition of the 3 major components of K+ currents IKpeak IKsus and IKur were independent of Ca2+ but rather involved CaMKII and the AMPK/NOS/PKG axis. Notably western blot showed that EPAC1 but not EPAC2 was overexpressed in the atria of AF patients. A post-treatment of SR myocytes with AM-001 failed to reverse the 8-CPT-AM-induced effect on K+ currents in SR cardiomyocytes while it corrected the EPAC-dependent downregulation of IK in AF cardiomyocytes. Our results uncover that EPAC activation influences IK by CaMKII and AMPK/NOS/PKG signaling in human atrial myocytes. Our findings highlight that EPAC1 over-activation in AF cardiomyocytes promotes the electrophysiological remodeling underlying the initiation of AF.