Abstract 509: Early Pathogenesis of Murine Aortic Valve Disease is Marked by Versican-Rich Proteoglycan Synthesis
Bibliographic record
Abstract
Background: Aortic valve disease (AVD) is a cell-mediated pathology without pharmacotherapy whose early pathogenesis is poorly understood. In mice, the study of later-stage fibrotic & calcific AVD requires aggressive dietary/genetic induction unsuitable for the study of early AVD progression. Here, we examined the initial extracellular matrix & cellular changes induced in the mouse aortic valve by a mildly atherogenic diet. Methods: Male WT C57Bl/6J mice were fed control or high-fat (HF, BioServ F3282) diets for 4 or 16 months (n = 6-10 per group). Aortic valve function was assessed by echocardiography. Valve sections were (immuno)stained for Movat’s pentachrome, proteoglycans (PG), Sox9, & αSMA. Valve interstitial cells (VICs) from porcine aortic valves were cultured with 5 ng/ml TGF-β1 for 5 days. PG synthesis & mRNA levels were measured by g-HCL & qPCR, respectively. Results: At 4 months, valve function was unaffected by the HF diet (transvalvular velocity: 123.5 ± 8.5 vs. 128.2 ± 9.2 cm/s, p = 0.75), & no leaflets expressed αSMA. Distal tips of HF leaflets were thickened (84.4 ± 10.4 vs. 37.3 ± 2.7 μm) due to PG accumulation (11435 ± 1920 vs. 5448 ± 762 μm 2 , p < 0.01), not collagen deposition (1729 ± 815 vs. 1771 ± 663 μm 2 , p = 0.87). Versican was the only PG increased in HF leaflets (2.38-fold, p < 0.05), with no alterations in decorin or biglycan (p = 0.69 & 0.59). Chondrogenic processes were activated in HF leaflets, with a 3.42-fold increase in Sox9-positive leaflet area (p < 0.01). By 16 months, HF mice had elevated transvalvular velocities (169.7 ± 20.3 vs. 115.4 ± 3.6 cm/s, p < 0.05) & leaflets were αSMA-positive & myofibrogenic. Histology of 16-month mice for PGs & Sox9 is ongoing. Early PG expression patterns were recapitulated in culture: total PG production was increased 2.14-fold in TGF-β1-treated VICs (p < 0.05), while versican mRNA was solely elevated (1.53-fold, p < 0.05) & decorin & biglycan were decreased (-2.05-fold, p < 0.01 & -2.62-fold, p < 0.05 respectively). Conclusions: Diet-induced de novo PG synthesis is versican-rich, occurs along with increased Sox9 expression, & develops prior to myofibroblast activation, fibrosis, or deficits in valve function. These studies provide new insight into early AVD pathogenesis & the involvement of specific PGs therein.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.006 | 0.002 |
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".