Implication of the histone methyltransferase EZH2 in pulmonary arterial hypertension
Bibliographic record
Abstract
Background: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by persistent elevation of pulmonary arterial (PA) pressure, which results in a striking increase in right ventricular (RV) afterload and subsequent failure. PA smooth muscle cells (PASMCs) from PAH patients exhibit a cancer-like hyperproliferative and apoptosis-resistant phenotype contributing to obliteration of the vascular lumen. Although epigenetic modifications are increasingly appreciated as an important contributing factor of PAH development, the precise mechanisms remain to be elucidated. EZH2 is a histone methyltransferase that is overexpressed in many cancers and is critical for cancer cell proliferation and survival. Thus, we hypothesized that EZH2 expression is up-regulated in PAH-PASMCs leading to vascular remodeling in PAH. Aim: We aim to demonstrate that up-regulation of EZH2 in PAH-PASMCs promotes vascular remodeling in PAH. Methods and Results: Using Western blot (WB), we showed that EZH2 is upregulated in lungs, distal PAs and isolated PASMCs from PAH patients (p<0.01) compared to controls. EZH2 expression was also increased in human compensated RV but was decreased in PAH patients with decompensated RV failure. Similar results were found in the monocrotaline (MCT) rat model. Pharmacological (GSK126 or EPZ-6438) or molecular (siEZH2) inhibition of EZH2 leads to reduced PAH-PASMC proliferation (Ki67 labeling and EdU assay, p<0.001) and resistance to apoptosis (Annexin V assay p<0.001). This effect was associated with decreased expression of Survivin (WB, p<0.05). Conclusion: We provide evidence that EZH2 is implicated in PAH and contributes to the cancer-like phenotype of PAH-PASMCs.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".