Abstract 150: Targeting The Lipogenic Enzyme ATP Citrate Lyase As A Potential Therapy Against Coronary Artery Disease
Bibliographic record
Abstract
Introduction: Coronary artery disease (CAD) such as coronary stenosis and intra vein graft stenosis are characterized by a cancer-like pro-proliferative and apoptosis-resistant phenotype of smooth muscle cells (SMCs), fueled by a metabolic shift toward glycolysis and interconnected global changes in the epigenetic landscape. The nucleo-cytoplasmic enzyme ATP Citrate Lyase (ACLY) has recently emerged as a key player and therapeutic target in cancer by favoring Warburg effect, lipid synthesis and chromatin remodeling. However, its role in CAD is still unknown. We hypothesized that ACLY is upregulated in CAD and supports the abnormal phenotype of CAD-CoASMCs. Methods and Results: ACLY expression positively correlates with vascular remodeling (aSMA labeling) in human distal coronary artery (CoAs, p<0,01) as well as in dog saphenous vein (SV) graft from bypass surgery (p<0,05). Increased expression and activation (phosphorylation) of ACLY were also observed in CoASMCs isolated from CAD patients (immunoblot, p<0,01) with preferential localization in the nucleus (immunofluorescence ACLY labelling (p<0,001)). Pharmacological (BMS303141) or molecular (siRNA) ACLY inhibition resulted in decreased survival, proliferation (immunoblot: PCNA, MCM2 and SURVIVIN (p<0,05) & immunofluorescence Ki67 and Annexin V labelling (p<0,001)), histones acetylation (immunoblot: acH3K27 and acH4 (p<0,05)) and reversed Warburg effect (immunoblot: pPDH, LDHA, PFKBP3 (p<0,01) & seahorse assays (p<0,05)) of CAD-CoASMC. RNA sequencing analysis showed that ACLY molecular inhibition in CAD-CoASMC mostly affectes cell cycle and cell proliferation pathways. Ex-vivo, ACLY inhibition attenuates vascular remodeling (EVG staining) in human CoAs and SVs rings denuded of endothelial cells and exposed to growth factors (p<0,05). In vivo, SMS-targeted loss of Acly in mice model of carotid artery denudation injury prevents vascular remodeling (p<0,05). Same results are observed with pharmacological inhibition of ACLY (BMS303141 & bempedoic acid) in carotid artery wire injury rat model (p<0,05). Conclusion: We demonstrated that ACLY is implicated in vascular remodeling in CAD and its Pharmacological inhibition may represent a novel avenue as therapeutic treatment.
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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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.008 | 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".