DOI: 10.1161/circ.148.suppl_1.17836 ISSN: 0009-7322

Abstract 17836: ATP Citrate Lyase Coordinates Lipid Synthesis and Expression Cell Cycle Regulating Genes to Promote Vascular Remodeling in Pulmonary Arterial Hypertension

Charlotte Romanet, Yann Grobs, Sarah-Eve Lemay, Alice Bourgeois, Tsukasa Shimauchi, MABROUKA SALEM, Sandra Martineau, Sandra Breuils Bonnet, Melanie Sauvaget, Charlie Theberge, Francois Potus, Steeve Provencher, Olivier Boucherat, Sebastien Bonnet
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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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