Abstract 19388: HDAC6 Inhibition Potential in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a progressive and fatal disease characterized by the elevation of mean pulmonary arterial pressure. Pulmonary arterial smooth muscle cells (PASMCs) from PAH patients exhibit a cancer-like pro-proliferative and anti-apoptotic phenotype leading to development of progressive pulmonary artery remodeling. The histone deacetylase 6 (HDAC6) is mainly cytoplasmic and involved primarily in “non-histone” functions. Previous studies have shown that HDAC6 plays critical roles on many cellular processes related to cancer. Hypothesis: HDAC6 inhibition corrects the abnormal phenotype of PAH-PASMCs and improves PAH. Methods and Results: Using a multidisciplinary and translational approach, we demonstrated that HDAC6 is upregulated (WB; p In vitro , inhibition of HDAC6 increases DNA damage (γH2AX, WB) and promotes the accumulation of ubiquitinated protein aggregates potentially toxic for the cell (ubiquitin, WB and IF). Finally, in both monocrotaline and sugen/hypoxia rat models of PAH, we demonstrated that HDAC6 inhibition using Tubastatin A (25mg/kg/day, 14 days, i.p.) improves pulmonary hemodynamic (p Conclusions: We provide evidence that HDAC6 is upregulated in human PAH and contribute to the proliferative and anti-apoptotic phenotype of PAH-PASMCs. HDAC6 inhibition may represent a novel and attractive avenue for reversing PAH avoiding the adverse off-target effects of pan-HDAC inhibitors. The susceptibility of HDAC6 KO mice to develop PAH following hypoxia exposure is currently under investigation.
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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) | 0.000 | 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) | 0.010 | 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".