Abstract 17836: ATP Citrate Lyase Coordinates Lipid Synthesis and Expression Cell Cycle Regulating Genes to Promote Vascular Remodeling in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of distal pulmonary arteries (PAs) due to enhanced proliferation, suppressed apoptosis and increased migration of PA smooth muscle cells (PASMCs). Like cancer cells, this abnormal phenotype of PASMCs is driven by epigenetic reprogramming and fueled by a metabolic shift towards glycolysis. ATP-Citrate Lyase (ACLY) is a nuclear-cytosolic enzyme that converts citrate to acetyl-CoA, which serves as substrate for histone acetyltransferases regulating gene expression and as a building block for lipid synthesis (required for proliferating cells to generate membrane). ACLY has recently emerged as a key player and therapeutic target in cancer. However, its role in PAH is unknown. METHODS/RESULTS: ACLY, p-ACLY (active form) expression and its nuclear localization were increased in distal PAs and PASMCs from PAH patients (WB and IF, p<0.01). Similar results were observed in the Sugen/Hypoxia (Su/Hx) animal models. In vitro , ACLY inhibition (BMS, siRNA) decreases PAH-PASMCs proliferation (PLK1; Ki67; p<0,01) and survival (Survivin; Annexin-V; p<0.01). These effects were accompanied with a decreased glycolysis (PFKBP3, p-PDH) and increased OCR/ECAR (Seahorse). Moreover, ACLY inhibition decreases the PAH-PASMCs migratory potential. Using RNA-Seq, we demonstrated that inhibition of ACLY downregulates genes associated with cell division and lipid synthesis. Further experiments revealed that ACLY promotes nuclear acetyl-CoA production favoring acetylation of H3K27, H3K9, H4, and GCN5-mediated transcriptional activation of genes responsible for cell cycle progression. Accordingly, we demonstrated that GCN5 inhibition decreases proliferation and survival of PAH-PASMCs (Ki67, AnnexinV). In vivo , Acly loss-of-function targeted to SMCs conferred protection against Su/HX-induced PAH in mice (echo and RHC). Accordingly, pharmacological inhibition of ACLY using BMS-303141 or Bempedoic Acid improved hemodynamics (RVSP, mPAP, SV, TPR, p<0.05) and vascular remodeling (EVG, p<0.05) in Su/Hx rats with established PAH. CONCLUSION: We demonstrated that ACLY inhibition may represent a novel therapeutic avenue to improve vascular remodeling in PAH.
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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) | 0.011 | 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".