Abstract 10759: Atp Citrate Lyase: An Attractive Target at the Nexus of Metabolic and Epigenetic Alterations in Pulmonary Arterial Hypertension
Bibliographic record
Abstract
Introduction: Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of distal pulmonary arteries (PAs). As in cancer, excessive proliferation and resistance to apoptosis of PA resident cells (especially PA smooth muscle cells, PASMCs), fueled by metabolic aberrations (metabolic shift toward glycolysis) and interconnected global changes in the epigenetic landscape is a pivotal component of severe PA remodeling, for which current pharmacotherapies have limited efficacy. ATP Citrate Lyase (ACLY), a nuclear cytosolic enzyme that converts citrate to Acetyl-CoA, 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 PAH is unknown. We hypothesized that ACLY is upregulated in PAH and supports the abnormal phenotype of PAH-PASMCs. Methods/Results: Increased expression and nuclear localization of ACLY were observed in lungs and isolated PASMCs from PAH patients compared to controls (n=10, p<0.05; immunoblot and immunofluorescence). Similarly, ACLY was upregulated in PAH animal models (Su/Hx rats and mice). We found that pharmacological or molecular (siRNA) inhibition of ACLY impedes PAH-PASMC bioenergetics (as assessed by TMRM, expression of glycolytic enzymes and seahorse) and decreased P300-dependent histone H3 and H4 acetylation. Consistently, inhibition of ACLY was accompanied by 1) a decrease in proliferation (Ki67 labeling, n=8, p<0.05), 2) an increase in apoptosis (Annexin V and TMRM, n=8, p<0.05) and 3) a downregulation of P300-regulated pro-proliferative/anti-apoptotic factors (western blot of PCNA, Survivin, PLK1 and STAT3). In vivo, inhibition of ACLY using ETC-1002 in both male and female Su/Hx-challenged rats with established PAH resulted in a significant improvement in pulmonary vascular remodeling and right ventricular function (RVSP, mPAP, TAPSE, S-Wave, SV by echocardiography and catheterization). Furthermore, we found that inactivation of Acly targeted to smooth muscle cells confers protection in a gene-dosage-dependent manner against Su/Hx-induced PAH in mice. Conclusion: We demonstrated that the inhibition of ACLY is a novel and attractive therapeutic strategy to reverse 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) | 0.001 | 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) | 0.012 | 0.003 |
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".