Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling

Aims Heart failure (HF) produces left atrial (LA)-selective fibrosis and promotes atrial fibrillation. HF also causes adrenergic activation, which contributes to remodelling via a variety of signalling molecules, including the exchange protein activated by cAMP (Epac). Here, we evaluate the effects of Epac1-signalling on LA fibroblast (FB) function and its potential role in HF-related atrial remodelling. Methods and results HF was induced in adult male mongrel dogs by ventricular tachypacing (VTP). Epac1-expression decreased in LA-FBs within 12h (-3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 mu M) reduced, whereas the Epac blocker ESI-09 (1 mu M) enhanced, collagen expression in LA-FBs. Norepinephrine (1 mu M) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The -adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (2-AR-blocker), but not by CGP (1-AR-blocker). -AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the 2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-1, known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3-inhibitor SIS3. To evaluate effects on atrial fibrosis in vivo, mice subjected to myocardial infarction (MI) received the Epac-activator Sp-8-pCPT or vehicle for 2weeks post-MI; Sp-8-pCPT diminished LA fibrosis and attenuated cardiac dysfunction. Conclusions HF reduces LA-FB Epac1 expression. Adrenergic activation has complex effects on FBs, with -AR-activation suppressing Epac1-expression and increasing collagen expression, and 2-AR-activation having opposite effects. Epac1-activation reduces cardiac dysfunction and LA fibrosis post-MI. Thus, Epac1 signalling may be a novel target for the prevention of profibrillatory cardiac remodelling.