July 14, 2018Cardiovascular ResearchOpen Access

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

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Why the study?

Does Epac1 activation reduce left atrial fibrosis and cardiac dysfunction in preclinical models of heart failure?

Structured PICO

Does Epac1 activation reduce left atrial fibrosis and cardiac dysfunction in preclinical models of heart failure?

Population

Adult male mongrel dogs with heart failure induced by ventricular tachypacing (VTP), mice subjected to myocardial infarction (MI), and isolated left atrial fibroblasts.

Intervention

Epac1 activation (in vitro with 8-pCPT, in vivo with Sp-8-pCPT for 2 weeks post-MI)

Comparator

Vehicle or control conditions

Outcome

Left atrial fibrosis and cardiac dysfunctionsurrogate

Epac1 signaling regulates atrial fibroblast function, and its activation reduces left atrial fibrosis and cardiac dysfunction in preclinical models, highlighting a potential therapeutic target for profibrillatory remodeling.

Implication

Epac activation attenuates post-MI remodeling in mice; leaves open Epac1 as therapeutic target in human HF.

Abstract

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 12 h (-3.9-fold) of VTP onset. The selective Epac activator, 8-pCPT (50 µM) reduced, whereas the Epac blocker ESI-09 (1 µM) enhanced, collagen expression in LA-FBs. Norepinephrine (1 µM) decreased Epac1-expression, an effect blocked by prazosin, and increased FB collagen production. The β-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (β2-AR-blocker), but not by CGP (β1-AR-blocker). β-AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the β2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-β1, 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 2 weeks 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 α-AR-activation suppressing Epac1-expression and increasing collagen expression, and β2-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.