Abstract 4136511: Targeting ATP Citrate Lyase: A Novel Therapeutic Strategy for Vascular Remodeling in Pulmonary Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by a progressive obliteration of distal pulmonary arteries (PA), 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 PAH remains unknown. We hypothesized that ACLY is upregulated in PAH and supports the abnormal phenotype of PAH-PASMCs . Methods/Results: To investigate this hypothesis, we measured ACLY expression in human distal pulmonary arteries and isolated PASMCs from PAH patients (immunoblot/Immunofluorescence). We found increased expression and activation of ACLY in PAH-PASMCs, with preferential localization in the nucleus. Inhibition of ACLY using BMS-303141 or siACLY decreased PAH-PASMCs proliferation (Ki67/MCM2, PLK1, PCNA) and survival (Annexin V/SURVIVIN). ACLY inhibition also reduced glycolysis markers and increased mitochondrial respiration. Additionally, the inhibition of ACLY lowered cholesterol levels and lipid droplet accumulation in PAH-PASMCs. 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 significantly improved pulmonary vascular remodeling (Elastica Van Gieson staining, EVG) and right ventricular function (RVSP, mPAP, TAPSE, S-Wave, SV by echocardiography and right heart catheterization) in Su/Hx-challenged rats with established PAH. SMC-specific Acly K.O mice were protected against Su/Hx-induced PAH. Consistently, tamoxifen-induced SMC-specific Acly deletion improved hemodynamics parameters in Su/Hx mice. These therapeutic effects were associated with a reduced acetylation of H3K27 and H3K9 (IF). Ex vivo , inhibition of ACLY attenuated vascular remodeling (EVG) in human precision cut lung slices exposed to a growth factor cocktail. Conclusion: Our study reveals that ACLY plays a critical role in vascular remodeling in PAH and its pharmacological inhibition may represent a novel and attractive 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 | 0.002 |
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".