Dataset Information

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

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 ?-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 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 ?-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.

SUBMITTER: Surinkaew S

PROVIDER: S-EPMC6302269 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Surinkaew Sirirat S Aflaki Mona M Takawale Abhijit A Chen Yu Y Qi Xiao-Yan XY Gillis Marc-Antoine MA Shi Yan-Fen YF Tardif Jean-Claude JC Chattipakorn Nipon N Nattel Stanley S

Cardiovascular research 20190101 1

<h4>Aims</h4>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.<h4>Methods and results</h4>HF was induced in adult male mongrel dogs by ventricular ...[more]

PMID: 30016400

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Project description:Background and aimsFibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1△HBS ) against NAFLD.Approach and resultsFGF1△HBS administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased. FGF1△HBS reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1△HBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1△HBS . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1△HBS antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1△HBS benefits on both oxidative stress and lipid metabolism that were FGF receptor (FGFR) 4 dependent. Further support of these in vitro findings is that liver-specific AMPK knockout abolished therapeutic effects of FGF1△HBS against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1△HBS improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice.ConclusionsThese findings indicate that FGF1△HBS is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.

Dataset Information

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

Aims

Methods and results

Conclusions

Publications

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

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