Abstract 14172: Abrogation of S100A1 Exacerbates Right Ventricular Dilation and Fetal Gene Expression in the Sugen/hypoxia Model of Pulmonary Arterial Hypertension in Mice
Bibliographic record
Abstract
Background: S100A1, a Ca 2+ -sensor protein, is expressed in myocardium and endothelial cells and regulates cardiac muscle contractility. Previously, we demonstrated that under basal conditions in vivo , S100A1 knockout mice (KO) exhibited a significant elevation in right ventricular systolic pressure (RVSP), accompanied by an increase in RV hypertrophy. Since RV dysfunction occurs with progression of pulmonary arterial hypertension (PAH), we aimed to determine the impact of deleting S100A1 on progression of PAH in the Sugen-hypoxia (SUHx) model in mice. Methods and Results: C57BL6 (WT) and S100A1 KO mice (n=10 per group) were injected once weekly subcutaneously with SU (20mg/kg) and exposed to chronic Hx (10% O 2 ) for 3 weeks. PAH was assessed by hemodynamic parameters, RV morphology and echocardiography. RV and lung tissue were collected for molecular analysis. In WT and S100A1 KO mice exposed to SUHx, RVSP was similar 31.0±1.90 vs.31.4±2.08, respectively. In RV and lung tissue of WT mice, S100A1 mRNA and protein decreased approximately 40% in response to SUHx. SUHx induced similar increases in RV weight calculated as the Fulton index (0.43±0.06 in WT vs. 0.41±0.04 in S100A1KO) but in contrast to WT, S100A1 KO demonstrated a 3.7- and 1.5- fold increase in the mRNA levels of the hypertrophic genes, atrial natriuretic factor and beta-myosin heavy chain, respectively (p<0.05). In S100A1 KO mice SUHx reduced heart rate (S100A1KO - 305.41±54.69 vs. WT- 443 ±54.82 bpm, p< 0.001) compared to WT. Furthermore, serial echocardiographic assessment indicated increased RV dilation in the S100A1KO compared to the WT in response to SUHx as assessed by increases in RV internal diameter in both diastole (S100A1KO, 1.92±0.08 vs. WT, 1.53 ±0.08, p=0.004) and systole (S100A1KO, 1.34±0.1 vs. WT, 0.97±0.01, p=0.02). Conclusion: Our results show that PAH is associated with decreased expression of S100A1 in the RV and lack of S100A1 increases RV dilation and expression of fetal gene markers in the SUHx model. S100A1 may serve to limit severity of RV structural changes in PAH and represents a potential therapeutic target in this disease.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".