Targeting ATP Citrate Lyase to mitigate Vascular Remodeling Pathogenesis.
Bibliographic record
Abstract
Pulmonary arterial hypertension (PAH) is a progressive occlusive vascular disease (OVD) in which pulmonary artery (PA) smooth muscle cells (PASMC) are characterized by excessive proliferation and resistance to apoptosis, like in cancer cells. These features are shared with neointimal hyperplasia in coronary artery disease (CAD). ATP citrate lyase (ACLY), has recently emerged in cancer as a key player to sustain cellular proliferation and survival by favoring Warburg effect, chromatin acetylation, and lipid synthesis. However, its role in OVD remains unknown. Thus, we hypothesized that ACLY is upregulated in OVD and supports the proliferative phenotype of OVD-SMCs. Increased expression and nuclear localization of ACLY were observed in 1) VRD-SMCs from both PAH and CAD patients compared to controls (immunoblot, IB; immunofluorescence, IF) and 2) in PAH and CAD rodents models (SugenHypoxia, SuHx and carotid injury, CI). ACLY inhibition impedes OVD-SMC bioenergetics and lipid metabolism (OCR/ECAR ratio, RNASeq) and decreased nuclear acetyl CoA, histones acetylation reducing SMC proliferation and survival (Ki67 and AnnexinV by IF, PCNA and Survivin by IB). In vivo, pharmacological inhibition of ACLY significantly improved pulmonary hemodynamics / remodeling in SuHx rats and neointimal hyperplasia in CI rats. Smooth muscle specific Acly K.O mice were resistant to both PAH and CI. In conclusion, we demonstrated that inhibition of ACLY may represent a novel and attractive therapeutic avenue for OVD. Both Y. Grobs and C. Romanet equally contributed
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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) | 0.001 | 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".