HDAC6‐Hsp90 interplay in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Background 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 metabolic‐dependent pro‐proliferative, pro‐migratory 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. HDAC6 interacts and deacetylates various proteins such as α‐tubulin and Hsp90 promoting proto‐oncogene activation such as Survivin (implicated in PAH) to carry out cancerous functions. We hypothesize that HDAC6/Hsp90 axis is up‐regulated in PAH and contributes to the development of the cancer‐like phenotype through in part Survivin stabilization. Method/Results Using a translational molecule‐cell‐organ‐animal and multidisciplinary approach, we demonstrated that both HDAC6 and HSP90 are up‐regulated (immunofluorescence and immunoblot; p<0.01) in the lungs and PASMCs isolated from PAH patients (n=5) compared to age‐matched controls (n=5). HDAC6 inhibition via a pharmacological (Tubastatin A) or molecular (siHDAC6) approach dose dependently increased α‐tubulin acetylation and decreased PAH‐PASMC migration (wound healing assay; p<0.05), resistance to apoptosis (Annexin‐V; p<0.05) and proliferation (Ki67; p<0.01). Increased apoptosis following Tubastatin A treatment was associated with mitochondrial membrane depolarization (TMRM) of PAH‐PASMCs and inhibition of the oxygen consumption rate in a concentration‐dependent manner (Seahorse XFe 24 system). All these effects were associated with a down‐regulation of Survivin. Similarly, inhibition of Hsp90 (AT13387 or siHsp90) reverses the cancer‐like phenotype and this effect was associated with a down‐regulation of HDAC6, suggesting that HDAC6 up‐regulation in PAH is Hsp90‐mediated. In vivo, HDAC6 inhibition in monocrotaline‐induced PAH decreases both mean pulmonary artery pressure (right heart catheterization, p<0.01) and right ventricular hypertrophy (Fulton index). Conclusion We provide evidence that Hsp90 and HDAC6 are specifically up‐regulated in human PAH and contributes to the proliferative, migratory and anti‐apoptotic phenotype seen in PAH‐PASMCs. As HDAC6 inhibitors have been tested in cancer, this offers a short‐term new therapeutic avenue for PAH patients. Support or Funding Information Canada Research Chairs and CIHR grants to S. Bonnet and S. Provencher supported this work
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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".