Epac2-Rap1 Signaling Regulates Reactive Oxygen Species Production and Susceptibility to Cardiac Arrhythmias.

AIMS:-adrenergic signaling involves cyclic adenosine monophosphate (cAMP) acting via both protein kinase-A and exchange protein directly activated by cAMP (Epac): a guanine nucleotide exchange factor for the small GTPase Rap1. Inhibition of Epac-Rap1 signaling has been proposed as a therapeutic strategy for both cancer and cardiovascular disease. However, previous work suggests that impaired Rap1 signaling may have detrimental effects on cardiac function. The aim of the present study was to investigate the influence of Epac2-Rap1 signaling on the heart using both in vivo and in vitro approaches. RESULTS: or the mitochondria-targeted antioxidant, mitoTEMPO. In vivo, inhibition of Epac2 caused ventricular tachycardia, torsades de pointes, and sudden death. The in vitro and in vivo effects of Epac2 inhibition were mimicked by inhibition of geranylgeranyltransferase-1, which blocks interaction of Rap1 with downstream targets. INNOVATION: provides a promising strategy to prevent arrhythmias caused by impaired Epac2-Rap1 signaling. CONCLUSION:Epac2-Rap1 signaling attenuates mitochondrial production and reduces myocardial arrhythmia susceptibility. Antioxid. Redox Signal. 27, 117-132.

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