Abstract 15608: Atp Citrate Lyase a New Signaling Hub Between Metabolism and Epigenetic in Vascular Remodeling and Right Ventricle Failure in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Objective: Pulmonary arterial hypertension (PAH) is a lung disease characterized by vascular lesions and obstruction of distal pulmonary arteries (PA) leading to right ventricle (RV) remodeling and death. Similar to cancer cells, PA smooth muscle cells (PASMCs) exhibit an excessive proliferation and resistance to apoptosis, pivot components of vascular remodeling, due to epigenetic reprogramming and Warburg effect. This epigenetic/metabolic signature is attributed in part to the upregulation of ATP citrate lyase (ACLY). By decreasing cytosolic levels of citrate, ACLY supports glycolysis, while by generating acetyl-coA in the nucleus it promotes histone acetylation and signaling pathways supporting pathological processes like proliferation, hypertrophy, and fibrosis, pathological features in PAH. In the cytosol, ACLY controls the synthesis of lipids required for proliferating cells to generate membranes. We thus hypothesized that ACLY is upregulated in PAH and contributes to PA remodeling and RV failure. Methods/Results: Using immunoblot, we showed an upregulation of ACLY in human distal PA and isolated PASMCs from PAH patients (p<0.05 ; n=10), like in Sugen/Hypoxia rat model. In vitro, pharmacological inhibition of ACLY significantly decreased PAH-PASMC proliferation (Ki67 labeling), resistance to apoptosis (Annexin V and caspase 3 assays) and restored a proper metabolism (seahorse assay) (p<0.05 ; n=5). Mechanistically, we showed that ACLY inhibition decreases P300-dependent pro-survival factors including Survivin, PCNA, cMYC, PKM2, phospho-PDH / PDH, and restores FOXO3 and AMPK functions know to be decreased in PAH. Besides, we found that ACLY expression was upregulated in failed RV from rats subjected to pulmonary artery banding; its expression correlating negatively with stroke volume and positively with RVEDP; hypertrophy and fibrosis. Conclusion: Our preliminary data suggest that ACLY contributes to vascular remodeling in PAH. Current experiments aim to demonstrate whether 1) pharmacological inhibition of ACLY reverses PAH in animal models and 2) whether inactivation of Acly targeted to smooth muscle cells and cardiomyocytes improves pulmonary vascular remodeling and RV dysfunction, respectively.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.016 | 0.005 |
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".