Abstract 18853: Rescue of Pulmonary Hypertension-Induced Right Ventricular Failure by Silencing Snai1 Induces Alterations in Methylation Status of Critical Genes Regulating Endothelial-to-Mesenchymal-Transition and Fibrosis
Bibliographic record
Abstract
Introduction: Pulmonary hypertension (PH)-induced RV failure (PH-RVF), a significant prognostic determinant, is characterized by RV endothelial-to-mesenchymal transition (EndMT), fibrosis, and remodeling. However, the regulatory control of RV EndMT and fibrosis remains unclear. Hypothesis: TGFβ1-Snai1-LOXL2 axis regulates RV EndMT and fibrosis in PH-RVF. Key gatekeeper transcription factor (TF) Snai1 mediates RV EndMT and fibrosis via differential methylation changes in EndMT and fibrotic genes and may serve as a novel therapeutic target. Methods: Male rats received s.c. Monocrotaline (MCT, 60mg/kg, n=9; 30-days), Sugen (20mg/kg, n=9; 3-wk hypoxia+2-wk normoxia; SuHx) or PBS (CTRL, n=9). For Snai1-knockdown (KD), MCT rats received siSnai1 (n=6; 5nM every 3-4d, IV) or scramble (n=7) from day 14-30. Echo, cath, RV-RNASeq, qPCR, WB, IF validation, and RV-DNA methylome RRBS-Seq were performed. Differentially methylated sites (DMS) and regions (DMR) were assessed. Secondary RNASeq analysis was performed on human decompensated-RVF vs Control (dRVF; GSE198618) and human RVs were assessed for EndMT, fibrosis, myofibroblast (MFB) transition, and Snai1+LOXL2. Snai1-KD was performed on human coronary artery endothelial cells (HCAECs) and human cardiac fibroblasts (HCFs) under hypoxia+TGFβ1. Results: MCT and SuHx had increased RVSP and Fulton index and decreased RVFAC (all p<0.001). RNASeq showed EndMT and Snai1 as the top-upregulated pathway and TF respectively in MCT and SuHx and human dRVF. RV EndMT, fibrosis, MFB transition, TGFβ1-Snai1-LOXL2, and peri-nuclear colocalization of Snai1+LOXL2 were increased in MCT, SuHx and dRVF patients. Snai1-KD rescued PH-RVF via significantly reducing Snai1+LOXL2. RV-RNASeq demonstrated EndMT as the top-downregulated pathway and decreased fibrotic DEGs. RV RRBS-Seq showed significant DMS and DMR remodeling of Dnmt3a, Kdm1a, Snai1, TGFβ1/2, and other critical EndMT and fibrotic genes. Snai1-KD inhibited hypoxia+TGFβ1-induced EndMT in HCAEC and MFB transition in HCF by decreasing Snai1+LOXL2 expression and reversing EndMT and fibrotic DEGs respectively. Conclusions: Rescue of PH-RVF by silencing Snai1 induces alterations in methylation status of critical genes regulating EndMT and fibrosis.
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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) | 0.005 | 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".