Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling.
Cardiovasc Res
; 115(1): 94-106, 2019 01 01.
Article
en En
| MEDLINE
| ID: mdl-30016400
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 andresults:
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 ß-adrenoceptor (AR) agonist isoproterenol increased Epac1 expression, an effect antagonized by ICI (ß2-AR-blocker), but not by CGP (ß1-AR-blocker). ß-AR-activation with isoproterenol decreased collagen expression, an effect mimicked by the ß2-AR-agonist salbutamol and blocked by the Epac1-antagonist ESI-09. Transforming growth factor-ß1, 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 ß2-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
1_ASSA2030
Problema de salud:
1_doencas_nao_transmissiveis
Asunto principal:
Fibrilación Atrial
/
Función del Atrio Izquierdo
/
Factores de Intercambio de Guanina Nucleótido
/
Fibroblastos
/
Remodelación Atrial
/
Atrios Cardíacos
/
Insuficiencia Cardíaca
/
Infarto del Miocardio
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Cardiovasc Res
Año:
2019
Tipo del documento:
Article
País de afiliación:
Canadá