Abstract 11625: Role of Wnts and Secreted Frizzled-Related Protein-1 in Atrial Fibroblast Pathophysiology During Atrial Fibrotic Remodeling
Bibliographic record
Abstract
Introduction: Left atrial (LA) fibroblasts (FBs) respond differentially vs left ventricular (LV) to fibrotic stimuli underlying LA selective fibrosis and atrial fibrillation (AF) in contexts like heart failure (HF). The most differentially expressed gene between LA and LV FBs (28 fold greater in LA) is secreted frizzled-related protein-1 (sFRP1), an endogenous Wnt antagonist. However, the role of sFRP1 and Wnt signaling in FB pathophysiology is unknown. Methods: HF-related LA remodeling was induced in dogs by ventricular tachypacing (VTP 240 bpm). mRNA and protein were quantified in freshly isolated FBs by qPCR (19 Wnt ligands) and immunoblot. Recombinant Wnt and sFRP1 proteins were used to assess effects on FBs; lentivirus-transferred small interfering RNA (siRNA) to knock down sFRP1. Results: AF duration, collagen1 and fibronectin expression increased at 1 and 2 wk VTP, paralleling LA fibrosis. Wnt2 and Wnt5a showed high FB expression. Wnt2 increased in LA FBs at 2 wks (4.8 fold) but did not change in LV (Fig A). Wnt5a decreased quickly in LA and LV (at 12 hrs, -8.9 and -2.9 fold) and remained decreased in LA up to 2 wks (Fig B). sFRP1 decreased at 12 and 24 hrs (-3.9 and -5.4 fold). Treatment of LA FBs with Wnt2 or Wnt5a increased cell size, collagen1 (1.7 and 1.8 fold) and fibronectin (31 and 2.1 fold) expression, and decreased sFRP1 mRNA (by 95% and 54%) (Fig C). Recombinant sFRP1 decreased fibronectin expression (-2.4 fold). Moreover, sFRP1 KD (85% reduction) increased Wnt2 and Wnt5a expression by 4.1 and 7.5 fold (Fig D), suggesting mutual negative interaction between sFRP1 and Wnt signaling in regulating ECM protein secretion. Conclusions: A variety of Wnt ligands are strongly and dynamically expressed in LA. Wnt2 and Wnt5a show countervailing changes during LA fibrosis development in HF, and negatively interact with sFRP1. Our results indicate complex regulation of atrial FB function by the Wnt system, which may provide novel therapeutic targets for AF-substrate prevention.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".