Implication of the Histone Deacetylase 6 in pulmonary arterial hypertension
Bibliographic record
Abstract
RATIONALE Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of complex etiology. Despite environmental stressful conditions, pulmonary artery (PA) smooth muscle cells (PASMCs) and endothelial cells (PAECs) exhibit a pro‐proliferative and anti‐apoptotic phenotype. Histone deacetylase 6 (HDAC6) is a cytoplasmic histone deacetylase overexpressed in response to stress and implicated in the regulation of multiple pro‐survival mechanisms in cancer cells. Therefore, we hypothesized that HDAC6 expression is increased in PAH‐PASMCs and PAH‐PAECs allowing them to survive and proliferate, thus contributing to vascular remodeling in PAH. OBJECTIVE Using a multidisciplinary and translational approach we aimed to demonstrate that HDAC6 inhibition is a promising strategy to improve PAH. METHODS AND RESULTS HDAC6 is significantly up‐regulated (immunoblot) in lungs, distal PAs, and isolated PASMCs and PAECs from 10 PAH patients and 15 experimental PAH animal (5 Sugen/hypoxia rats; 5 monocrotaline rats and 5 chronic hypoxic mice) compared to controls. Molecular (siRNA) and pharmacological inhibition (Tubastatin and ACY‐775) of HDAC6 reduces dose‐dependently PAH‐PASMC/PAEC proliferation (Ki67 assay) and resistance to apoptosis (Annexin V assay) in vitro sparing control cells. Mechanistically, we demonstrated that HDAC6 deacetylates Ku70, blocking the translocation of Bax to mitochondria and preventing apoptosis. In vivo inhibition of HDAC6 (Tubastatin A 25mg/kg/day for 2 weeks) significantly improved (n=5 to 10 p<0.05) established PAH by decreasing mean PA pressure, total pulmonary resistance and increasing cardiac output in two experimental models (Sugen/hypoxia and monocrotaline). In addition, we showed that HDAC6 inhibitor can be safely given in combination with currently approved PAH therapies (macitentan and tadalafil). Finally, Hdac6 K.O mice have significantly lower right ventricle systolic pressure in response to 3 weeks of chronic‐hypoxia compared to wild‐type mice. CONCLUSION We showed for the first time that HDAC6 is implicated in PAH development and represents a new promising therapeutic target to improve PAH. Support or Funding Information None
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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".