Exploring P300/CBP as therapeutic targets for pulmonary arterial hypertension and right ventricular failure
Bibliographic record
Abstract
Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery (PA) pressure and vascular remodeling, resulting in compensated hypertrophy and decompensated failure of the right ventricle (RV). The histone acetyltransferases P300/CBP are critical regulators in various cellular processes such as proliferation, apoptosis, hypertrophy, and fibrosis. Considering their pivotal role in modulating gene transcription, we hypothesized that P300/CBP contributes to maladaptive remodeling observed in PAH. Using western blot (WB) and immunofluorescence (IF), we show increased P300/CBP expression in isolated PA smooth muscle cells (PASMCs) and PAs from PAH patients compared to controls (p<0.01) as well as in monocrotaline (MCT) and sugen-hypoxia rat (p<0.05). Similarly, P300 expression is elevated in remodeled RV from PAH patients, MCT- and pulmonary artery banding- rats (PAB). In vitro, P300/CBP inhibition (CCS-1477 or siRNA) decreases PAH-PASMC proliferation and resistance to apoptosis [WB (PCNA, PLK1, Survivin) IF (Ki67, AnexinV)], prevents phenylephrine-induced hypertrophy (H9C2 cells, adult rat cardiomyocytes), and reduces activation (pSMAD2/3, aSMA, Fn, Col1A, MMP2, WB) and proliferation (PCNA, WB) of RV fibroblasts. In vivo administration of CCS-1477 in MCT rats reduces pulmonary vascular remodeling (Elastica Van Gieson), improves pulmonary hemodynamics (mPAP, RVSP) and attenuates RV fibrosis (Masson’s Trichrome (MT)). In the PAB rat model, CCS-1477 improves RV function (TAPSE, CO, SV) and reduces fibrosis (MT). Our finding suggests 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) | 0.003 | 0.001 |
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".