Abstract 11879: Control of Fibroblast Function by Adrenergic/EPAC System and Potential Role in Atrial Remodeling
Introduction: Heart failure (HF) produces left atrial (LA)-selective fibrosis and atrial fibrillation. HF also causes adrenergic activation, which contributes to remodeling via a variety of pathways mediated by altered signaling molecules, including the exchange protein activated by cAMP (Epac).
Hypothesis: To evaluate the effects of adrenergic receptor (AR) and Epac1 signaling on LA fibroblast (FB) function and its potential role in HF-induced atrial remodeling.
Methods: HF was induced in dogs by ventricular tachypacing (VTP, 240 bpm) for various periods. mRNA and protein expression were measured in freshly isolated LA FBs by qPCR and immunoblot, respectively.
Results: Epac1 expression decreased in LA FBs within 12 hrs (-3.9 fold) of VTP onset (Fig. A). The selective Epac activator, 8-pCPT (33 μM) reduced, whereas the Epac blocker ESI-09 (1 μM) enhanced, LA FB collagen expression (Fig. B). Norepinephrine (NE, 1 μM) decreased Epac1 expression, an effect blocked by prazosin, and increased FB collagen protein production (Fig. C). Isoproterenol (ISO) increased Epac1 expression (Fig. D), an effect antagonized by ICI (β2-AR antagonist, 2 μM), but not CGP (β1-AR antagonist, 2 μM). β2-AR activation with ISO decreased collagen expression (Fig. E), an effect mimicked by salbutamol (10 μM) and blocked by ICI but not CGP. Transforming growth factor (TGF) β1 (10 ng/ml), known to be activated in HF, suppressed Epac1 expression, an effect blocked by the Smad3 inhibitor SIS3 (Fig. F).
Conclusions: AR activation has complex effects on FBs, with NE/α-AR-activation suppressing Epac1 and increasing collagen expression, and β2-ARs having opposite effects. HF reduces LA FB Epac1 expression, likely via increased NE release from adrenergic nerve endings, along with TGF β1 activation. Epac1 signaling reduces FB collagen expression, so Epac1 downregulation in HF contributes to the atrial profibrotic milieu and may be a novel target for prevention of profibrillatory atrial remodeling.
Author Disclosures: S. Surinkaew: None. M. Aflaki: None. X.Y. Qi: None. Y. Sun: None. S. Nattel: None.
- © 2015 by American Heart Association, Inc.