Abstract 14331: Role for HDAC6 in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background: Pulmonary arterial smooth muscle cells (PASMCs) from pulmonary arterial hypertension (PAH) patients exhibit a pro-proliferative, pro-migratory and anti-apoptotic phenotype mediated, at least in part, by survivin overexpression, leading to the development of progressive pulmonary artery (PA) remodeling. This results in right ventricle (RV) hypertrophy and failure. For many years, the cytoplasmic class IIb histone deacetylase 6 (HDAC6), which mainly functions as a α-tubulin deacetylase has been understudied. Several cancer studies have demonstrated that HDAC6 cooperates with the Heat Shock Protein 90 (HSP90) and regulates many signaling pathways involved in cancer and PAH development. In the cardiovascular field, HDAC6 upregulation has been associated with heart failure. We hypothesized that specific HDAC6 inhibition corrects the abnormal phenotype of PAH-PASMCs and improves RV function. Method/Results: Using a multidisciplinary and translational approach, we demonstrated that both HDAC6 and HSP90 are upregulated (Wb; p<0.01) in the lungs, distal PAs, and PASMCs from PAH patients (n=5) compared to controls (n=5). HDAC6 inhibition using Tubastatin A dose-dependently increased α-tubulin acetylation and decreased PAH-PASMC migration (scratch test; p<0.05), apoptosis resistance (Annexin-V; p<0.05) and proliferation (Ki67; p<0.01). Tubastatin A also reduced the expression of survivin in PAH-PASMCs (Wb). Similar effects were observed after HSP90 inhibition with AT13387, which also reduced HDAC6 expression in PAH-PASMCs (Wb) suggesting that a HSP90-dependent mechanism may account for HDAC6 upregulation. Within the heart, HDAC6 was exclusively expressed in human decompensated RV from PAH patients (n=5) and not in control RV (Wb, p<0.01). Conclusion: We provide evidence that HSP90 and HDAC6 are upregulated in human PAH and contribute to the proliferative, migratory and anti-apoptotic phenotype of PAH-PASMCs. Moreover, HDAC6 is specifically increased in the RV of PAH patients, suggesting that specific HDAC6 inhibition may represent a novel and attractive target in PAH for the treatment of both PA remodeling and RV failure. The therapeutic potential of HDAC6 inhibition in a PAH rat model 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 | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.003 |
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".