Abstract 17548: Inhibition of Exchange Protein 1 Directly Activated by cAMP (Epac1) is Cardioprotective Against Ischemia-reperfusion Injury
Background and Objectives: Epac1 is a guanine nucleotide exchange protein that is directly activated by cyclic adenosine monophosphate (cAMP) in a protein kinase A independent manner. Ischemia/reperfusion (I/R) is accompanied and influenced by perturbations of the β- adrenergic receptor pathway which acts through cAMP dependent signaling cascade to modulate cardiac function and remodeling. The Epac1-Rap signaling pathway is a potent regulator of Ca2+ cycling, cardiac hypertrophy and fibrosis. However, Epac1 involvement during the process of cardiomyocyte death, during I/R remains unknown. The present study was designed to investigate the role of Epac1 inhibition during ischemic reperfusion.
Methods and Results: Isolated adult cardiomyocytes from Epac1 knock-out (KO) and wild-type (WT) littermates mice were exposed to hypoxia for 2 h and 4 h. Cell death was determined by Hoechst/Propidium Iodide staining. Our data show that hypoxia induced apoptosis/necrosis for 4 h was prevented in KO mice (32±2% vs 22±1%, p[[Unable to Display Character: ˂]]0.01). Consistently, the expression level of necroptosis markers (Rip1; Caspase 8; Caspase 3; Bax) were also inhibited in the Epac1 KO cardiomyocytes. In order to study the effect o f the Epac1 deficiency during myocardial infarction, the left anterior descending coronary artery was occluded for 45 min followed by 24 h of reperfusion in WT and Epac1 KO mice. We examined the area at risk by Evans blue and infarct size was evaluated by TTC staining. We found the infarct size was significantly decreased in the KO mice compared to the WT animals (53±4 % vs 33±4%, p<0.01) despite the same area at risk. Concomitantly, the i.v. infusion of a selective pharmacological inhibitor of Epac1 named CE3F4 (10 mg/kg), 5 min before the reperfusion reduced the myocardial infarct size in WT mice by 40%.
Conclusion: Epac1 inhibition confers resistance to ischemia/reperfusion injury, at least in part, via limiting cell death pathway in cardiomyocytes. CE3F4 and related compounds may serve as a basis for the development of new therapeutic drugs to limit myocardial infarction injury.
Author Disclosures: P. Sicard: None. L. Fazal: None. M. Bisserier: None. F. Lezoualc’h: None.
- © 2014 by American Heart Association, Inc.