Selective inhibition of Histone deacetylases reverses vascular remodeling and improves right ventricle function in pulmonary hypertension
Bibliographic record
Abstract
Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Longfonds and CVON Background Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodeling of pulmonary vessels, leading to increased vascular resistance and ultimately right ventricle (RV) failure. Disturbed BMPR2/TGFβ signaling is a driver of disease progression. Inhibition of Histone deacetylases (HDACs) using small molecule inhibitors attenuated vascular remodeling, however, they worsened RV function in animal models of PAH. Objectives The aim of this study is to validate if the selective HDAC inhibitor Quisinostat reverses pulmonary vascular remodeling and improves RV function. Methods and results We found that protein levels of HDAC1 are increased in the lungs of PAH patients. Treating microvascular endothelial cells (MVECs) and smooth muscle cells of PAH patients with Quisinostat significantly decreased TGF-β signaling and strongly decreased cell proliferation and the levels of inflammatory cytokines. In the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, Quisinostat reversed abnormal vascular remodeling and improved RV function. Furthermore, Quisinostat could be combined safely with the contemporary PAH standard of care. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding, and no systemic or cardiotoxic effects were observed. Conclusions Our data demonstrate that selective inhibition of HDACs reverses pulmonary vascular remodeling and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| 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) | 0.000 | 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 teacher head, 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".