Abstract 103: Acly Inhibition As A Novel Therapeutic Approach For Vascular Remodeling In Coronary Artery Disease
Bibliographic record
Abstract
Coronary artery (CoA) disease (CAD) is characterized by neointimal hyperplasia (NH), which is driven by a cancer-like pro-proliferative phenotype of smooth muscle cells (SMCs). A metabolic shift towards glycolysis and changes in the epigenetic landscape contribute to this abnormal phenotype. ATP Citrate Lyase (ACLY) is an enzyme that plays a role in promoting the Warburg effect, lipid synthesis, and chromatin remodeling in cancer. However, its role in CAD remains unknown. We hypothesized that ACLY is upregulated in CAD and supports the abnormal phenotype of CAD-CoASMCs. To investigate this hypothesis, we measured ACLY expression in human distal coronary arteries and isolated CoASMCs from CAD patients. We found increased expression and activation of ACLY in CAD-CoASMCs, with preferential localization in the nucleus. Inhibition of ACLY using BMS-303141 or siACLY decreased CAD-CoASMCs proliferation and survival. ACLY inhibition also reduced glycolysis markers and increased mitochondrial respiration. Additionally, ACLY inhibition lowered cholesterol levels and lipid droplet accumulation in CAD-CoASMCs. Further analysis showed that ACLY promotes nuclear acetyl-CoA production, leading to acetylation of specific histone proteins and GCN5-mediated transcriptional activation of genes involved in cell cycle progression. The transcription factor FOXM1 appeared to mediate this genetic signature. In vivo , pharmacological inhibition of ACLY using BMS-303141 attenuated NH in a rat model of carotid injury (CI). SMC-specific Acly K.O mice were protected against CI-induced NH. Consistently, tamoxifen-induced SMC-specific Acly deletion mitigated NH in mice subjected to CI. The therapeutic effects were associated with reduced histone acetylation. To assess the translational potential of our findings, we tested the effects of ACLY inhibition on ex vivo human coronary artery and saphenous vein explants stimulated with growth factors cocktail. We found that ACLY inhibition prevent NH development, supporting the potential of ACLY as a therapeutic target. In conclusion, our study reveals that ACLY plays a critical role 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) | 0.001 | 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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 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".