Role of ATP Citrate Lyase (ACLY) in Vascular Remodeling

Pulmonary arterial hypertension (PAH) is a progressive occlusive vascular disease (OVD) in which pulmonary artery (PA) smooth muscle cells (PASMC) are characterized by excessive proliferation and resistance to apoptosis, like in cancer cells. These features are shared with neointimal hyperplasia (NH) in coronary artery disease (CAD). ATP citrate lyase (ACLY), has recently emerged in cancer as a key player to sustain cellular proliferation and survival by favoring Warburg effect, chromatin acetylation, and lipid synthesis. However, its role in OVD remains unknown. Thus, we hypothesized that ACLY is upregulated in OVD and supports the proliferative phenotype of OVD-SMCs. Increased expression and nuclear localization of ACLY were observed in 1) OVD-SMCs from both PAH and CAD patients compared to controls and 2) in PAH and CAD rodent models (SugenHypoxia, SuHx and carotid injury, CI). Inhibition of ACLY decreased both proliferation and survival of OVD-SMCs and reduced expression of markers associated with glycolysis and lipids synthesis. ACLY’s inhibition also enhanced mitochondrial respiration and lowered cholesterol. Further analysis showed that ACLY promotes nuclear acetyl-CoA production, leading to histone acetylation and GCN5-mediated transcriptional activation of genes involved in cell cycle progression. In vivo, pharmacological inhibition of ACLY significantly improved pulmonary hemodynamics in SuHx rats and NH in CI rats. Smooth muscle specific Acly K.O mice were resistant to both PAH and NH. Ex vivo, inhibition of ACLY attenuated vascular remodeling in human PCLS and CoA rings exposed to a growth factors. In conclusion, we showed that inhibition of ACLY may represent a novel and attractive therapeutic avenue for OVD.