Abstract 9771: Novel Contribution of an Epigenetic Factor "g9a" in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a vascular disease characterized by an increased mean pulmonary artery (PA) pressure. Pulmonary artery smooth muscle cells (PASMCs) from PAH patients exhibit a “cancer-like” hyperproliferative and apoptosis-resistant phenotype leading to pulmonary vascular remodeling. It is believed that these alterations are influenced by epigenetic processes. However, it is still not clear which gene are the drivers. “G9a”, a histone methyltransferase, is known to be overexpressed in different types of cancer, promoting cell survival and proliferation. Given the similarities between PAH and cancer, we hypothesized that G9a could be implicated in PAH progression and pathogenesis. Methods and Results: Using Western blot (WB) and immunofluorescence (IF), we showed that G9a is significantly upregulated in distal PAs and isolated PASMCs from PAH patients (n= 6-14, p<0.01). Similarly, G9a was increased (p<0.05) in three PAH animal models: monocrotaline (MCT), fawn-hooded rat (FHR) and mice exposed to chronic hypoxia. In vitro, pharmacological G9A inhibition using BIX01294 reduces PAH-PASMC proliferation (Ki67/ EdU assays, p<0.001) and survival (Annexin V assay, p<0.001). Through RNA sequencing analysis conducted in PAH-PASMCs treated or not with BIX01294, we found that upregulated genes were significantly enriched in “cholesterol biosynthesis” and “autophagy”. Consistently, G9a inhibition was accompanied by an increased lipid accumulation and an impaired autophagy flux as evidenced by the appearance of numerous cytoplasmic vacuoles positive for LC3-II (IF, WB), the accumulation of yellow puncta in PAH-PASMCs expressing the RFP-GFP-LC3 fusion protein, the unaffected LC3-II expression after adding chloroquine and the defect in cathepsin B and D maturation (WB). Same results were seen with UNC0642, another G9A inhibitor. In vivo , we showed that BIX01294 significantly improved established PAH in FHR (reduced RVSP and mPAP, increased SV and CO, by right heart catheterization, and attenuated pulmonary vascular remodeling, p<0,001). Conclusion: We showed that G9a upregulation contributes to the pro-proliferative phenotype of PAH-PASMCs; and its inhibition represents a novel avenue to improve PAH.
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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 | 0.001 | 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".