AbstractsBiology & Animal Science

Cardiac arrhythmias remain a leading cause of mortality for patients afflicted by cardiac diseases, such as heart failure (HF). Sudden cardiac death is implicated in ~50% of deaths in HF, and remodeling of ion channels further leads to lethal arrhythmias. Neurohormonal activation plays a significant role in cardiac remodeling and progression of the disease. In this thesis, I investigated the role of exchange protein directly activated by cAMP (Epac) in cardiac remodeling.HF is associated with an increase in adrenergic drive, with plasma norepinephrine concentrations predictive of mortality outcomes. Reduction in the slowly activating delayed-rectifier potassium current (IKs) is commonly observed in HF-related remodeling and plays a role in arrhythmogenesis. I sought to identify the underlying mechanisms of IKs downregulation via sustained β-adrenergic stimulation. Using an in vitro guinea pig model, I identified a signaling pathway that proceeded through β1-adrenergic receptors and involved the activation of Epac1 protein. Epac1 increased intracellular calcium activation of the calcineurin/nuclear factor of activated T cell (NFAT) pathway to transcriptionally down-regulate the expression of KCNE1 subunits of IKs. Adenovirus-mediated knockdown of Epac1 in vitro demonstrated the central role of Epac 1 in regulating IKs in guinea pigs.In vivo administration of isoproterenol and a specific Epac activator significantly increased action potential duration, indicating repolarization abnormalities, while IKs, L-type calcium current (ICaL), and inward rectifier current (IK1) were significantly decreased. The signaling pathway identified in our in vivo study will assist in devising more effective approaches to prevent arrhythmias.HF is associated with fibrotic remodeling that creates a substrate for atrial fibrillation (AF). Fibroblasts regulate extracellular matrix (ECM) production and excess ECM deposition leads to fibrosis. Fibrosis is more prominent in the atrium and atrial fibroblasts are more responsive to fibrotic stimuli. I sought to determine the role of Epac in the fibrotic response. Epac1 expression was decreased in an experimental model of tachypacing-induced HF with AF. Incubation of atrial fibroblasts with a specific Epac activator decreased collagen mRNA expression. Profibrotic stimuli such as norepinephrine and TGFβ1 decreased Epac1 expression in atrial fibroblasts. Sustained β-adrenergic stimulation modulated collagen expression through activation of Epac1 via β2-adrenergic receptors. These findings demonstrated the different roles of Epac in cardiomyocytes versus fibroblasts in cardiac remodeling in the heart. Les arythmies cardiaques demeurent la principale cause de mortalité pour de nombreuses maladies cardiaques notamment l'insuffisance cardiaque (IC). La mort subite cardiaque est impliquée dans environ 50% des décès.Le remodelage ionique arythmogène provoque une altération des canaux ioniques qui participe de façon significative à l'apparition d'une arythmie fatale. L'activation neuro-hormonale joue…