Abstract 10759: Atp Citrate Lyase: An Attractive Target at the Nexus of Metabolic and Epigenetic Alterations in Pulmonary Arterial Hypertension

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.