Abstract 18286: Histone Acetyltransferase P300/CBP in Pulmonary Arterial Hypertension and Associated Right Ventricular Failure
Bibliographic record
Abstract
INTRODUCTION Pulmonary arterial hypertension (PAH) is defined by increased pulmonary artery (PA) pressure and vascular remodeling, partly due to excessive proliferation and survival of PA smooth muscle cells (PASMCs). Initially, RV hypertrophy allows adaptation to increased resistance, but as the disease progresses, maladaptive remodeling takes place, leading to RV failure and death. Current therapies aim to promote vasodilatation, but none of them directly targets pathological lungs or RV remodeling. The histone acetyltransferases P300/CBP have been identified as central players driving gene expression in various cellular processes such as proliferation/apoptosis and hypertrophy/fibrosis, all of which are critical features of pathological lung and RV remodeling in PAH. Given their role in controlling gene transcription programs, we hypothesized that P300/CBP contributes to maladaptive remodeling. METHODS & RESULTS We show by western blot (WB) and immunofluorescence (IF) increased P300 expression in isolated PASMCs and distal PAs from PAH patients compared to controls (p<0.01) as well as in monocrotaline (MCT) and sugen-hypoxia rat models (p<0.05). Similar results are observed in remodeled RV from PAH patients, MCT- and pulmonary artery banding-subjected rats (WB). In vitro, P300/CBP inhibition (CCS-1477 or siRNA) reduces H3K27 acetylation (WB, p<0.05) in PAH-PASMCs and RV fibroblasts (RVFbs). This effect is accompanied by a decrease in PAH-PASMC proliferation and resistance to apoptosis [WB (PCNA, PLK1, Survivin), IF (Ki67, AnexinV), p<0.01]. Similarly, P300/CBP inhibition reduces proliferation (WB, PCNA, Survivin) and activation/extracellular matrix production (WB, pSMAD2/3, aSMA, Fn, Col1, MMP2) in RVFbs. In addition, P300/CBP inhibition prevents phenylephrine-induced hypertrophy in H9C2 cells and adult rat cardiomyocytes (IF, p<0.05). In vivo, administration of CCS-1477 reduces pulmonary vascular remodeling (Elastica Van Gieson, p<0.05), improves pulmonary hemodynamics (p<0.01) and attenuates RV fibrosis (Masson’s Trichrome, p<0.05) in MCT rats with established PAH. Conclusion: We provide evidence that targeting P300/CBP may represent a promising avenue to tackle both lung and RV maladaptive remodeling in PAH.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".