Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling
Bibliographic record
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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.004 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".