Pharmacological activation of exchange protein directly activated by cAMP 1 (EPAC1) increases action potential duration in mouse atrial myocytes

Abstract

Atrial Fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide. Several mechanisms are known to be involved in AF development and sustainability, such as abnormal Ca2+ cycling and action potential (AP) duration. Molecules involved in these mechanisms are potential relevant therapeutic candidates. One of these candidates is the Exchange Protein directly Activated by cAMP 1 (EPAC1), which has been recently shown to increase arrhythmogenic activity in ventricular cardiomyocytes and to be related to AF in an EPAC1-/- mouse model. Although strong evidence suggests that EPAC1 is involved in cardiac arrhythmia in mice, its role in AF has not been fully investigated. To investigate the effect of EPAC1 pharmacological activation in the development of atrial arrhythmogenic activity. Atrial myocytes from EPAC1-/- and Wild Type (WT) mice were dissociated by enzymatic digestion. AP were recorded using the whole cell configuration of the patch clamp technique in the current clamp mode. To assess the selective role of EPAC1, EPAC proteins were acutely activated by superfusion of 8-CPT-AM, a preferential EPAC1 activator (10 μM) and inhibited by superfusion of AM-001 compound, an EPAC1 non-competitive selective inhibitor (20 μM). Activation of EPAC1 by 8-CPT-AM drastically increased AP duration at 90% of repolarization (APD90) by 106.6 ± 14.3% (vs control; p < 0.0001) in WT atrial myocytes. This effect was attenuated by AM-001 perfusion (APD90 decreased by 38.9 ± 8.3% vs 8-CPT-AM; P < 0.05). Interestingly, EPAC1 deleted cardiomyocytes displayed a lower APD90 increase (+42.3 ± 15.1% vs control; P < 0.01) after treatment by 8-CPT-AM than that of WT atrial myocytes ( P < 0.05). Concomitant treatment of EPAC-/- cells with 8-CPT-AM and AM-001 failed to influence the effect on APD90 compared to 8-CPT-AM alone ( P = 0.85). Our results show that EPAC1 activation is involved in the modulation of AP duration in mouse atrial myocytes. In addition, our data suggest that EPAC1 could participate in AF initiation and/or sustainability by promoting an arrhythmogenic ectopic activity. Therefore, EPAC1 may constitute a therapeutic target in AF management.