Abstract 10909: A Novel ATP Citrate Lyase-Dependent Metabolic-Transcriptional Axis in Pulmonary Arterial Hypertension

Abstract

INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by enhanced pulmonary artery smooth muscle (PASMC) proliferation and suppressed apoptosis. In cancer, the sustainability of this phenotype required metabolic adaptation (Warburg effect / lipid synthesis) influencing chromatin structure and gene expression. By producing Acetyl coA the ATP Citrate Lyase (ACLY) has emerged as a key player in cancer by favoring Warburg effect, lipid synthesis and histone acetylation. We hypothesized that ACLY is upregulated in PAH and supports PAH-PASMC proliferation and contributes to PA remodelling. METHODS/RESULTS: The implication of ACLY in PAH was demonstrated by 1) an upregulation (n=10 p<0.05) of its expression, activation (P-ACLY) and nuclear localization in human PAH lungs, PASMCs and experimental PAH models (sugen/hypoxia, Su/Hx rats and mice) compared to control (immunoblot/immunofluorescence); 2) mice with ACLY deleted in SMCs did not develop Su/Hx-induced PA remodelling and PAH (n=20 p<0.05). Mechanistically, ACLY inhibition (siRNA/BMS) decreased proliferation (Ki67/PCNA) and increased apoptosis (AnnexinV / Survivin) in PAH-PASMCs (n=8 p<0.05). These effects were associated with the inhibition of multiple genes linked to cell cycle, metabolism and lipid synthesis (RNAseq p<0.05 n=6) leading to a decrease (p<0.05) in Warburg effect (LDH, PKM2, P-PDH) and an increase in OCR/ECAR (seahorse). These findings were coupled with an inhibition of the histone acetyl-transferase P300 and histones H3/H4 acetylation. Motif enrichment analyses of transcriptomic datasets identified NFY, NFAT and FOXM1 (all involved in PAH and P300 regulated) as putative transcription factors implicated in ACLY-dependent gene regulation in PAH. This will be confirmed by CHIPseq/ATACseq. In vivo, effects of ACLY inhibitors (BMS/ETC1002) were assessed in rats with Su/Hx-PAH. Both decreased PA pressure, resistance, wall thickness and improved right ventricular functions (n=20; p<0.05) (Echo/catheterization). CONCLUSION: We uncovered a novel ACLY-dependent metabolic-transcriptional axis explaining how PASMCs proliferate and survive in PAH. ACLY inhibition is an attractive therapeutic strategy to improve PAH as ETC1002 is clinically advanced.