Abstract 9739: MicroRNA26 Regulation of TRPC3 Subunits Underlies Profibrillatory Fibroblast Activation in a Canine Atrial Fibrillation Model
Bibliographic record
Abstract
Background: Cardiac fibroblast (FB) proliferation and differentiation into extracellular matrix (ECM) secreting myofibroblasts contributes to AF-promoting fibrotic remodeling. We previously observed that Ca 2+ entry through transient receptor potential canonical 3 (TRPC3) channels regulates cardiac FB proliferation/differentiation. Here, we examined the potential involvement of TRPC3 in a canine AF model. Methods: Dogs kept continuously in AF for 1 week by pacing at 600 bpm (n=11) were compared to controls (CTL, n=11). Echocardiographic, hemodynamic and electrophysiological properties were studied in vivo. Left atrial (LA) FBs were isolated for nonselective cation current ( I NSC ) recording (patch clamp), cell cycle analysis (flow cytometry), protein (immunoblot) and mRNA (qPCR) expression. Results: AF increased LA diastolic area by 13%* (*p<0.05 vs CTL) and LA pressure by 150%* without LV dilation. AF also shortened atrial refractory periods from 98±4 to 79±5 ms* (BCL 150 ms) and prolonged spontaneously maintained AF duration from 26±8 to 937±209 s*. In freshly isolated FBs, I NSC sensitive to a TRPC3 selective blocker, pyrazole3 (Pyr3, 3 μ M) increased in AF by 89%*, indicating increased TRPC3 current. In freshly cultured FBs, the cell number increase-rate, the G2/M cell content (an index of cell division) and α-smooth muscle actin protein expression increased in AF by 185*, 33* and 154* % respectively, indicating increased proliferation and differentiation; in vitro treatment with Pyr3 (3 μ M) decreased these profibrotic indices by 78%*, 12%* and 74%* vs vehicle respectively. In fresh FBs, collagen-1 and -3 gene expression increased in AF by 1210%* and 750%* respectively, indicating increased ECM production. TRPC3 protein expression in fresh FBs increased in AF by 64%*; however, TRPC3 mRNA decreased by 44%*, suggesting epigenetic regulation by microRNA (miR). AF reduced FB expression of miR-26a, predicted to target and suppress TRPC3 translation, by 65%*. In vitro miR-26a knockdown upregulated TRPC3 protein by 54%*, mimicking AF effects. Conclusions: AF increases FB proliferation, differentiation and ECM gene expression by increasing TRPC3 subunit expression and current, likely by downregulating the TRPC3-targeting microRNA miR-26.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".