ATP citrate lyase drives vascular remodeling in systemic and pulmonary vascular diseases through metabolic and epigenetic changes

ATP citrate lyase (ACLY), a crucial enzyme in de novo lipid synthesis and histone acetylation, plays a key role in regulating vascular smooth muscle cell (VSMC) proliferation and survival. We found that human coronary and pulmonary artery tissues had up-regulated ACLY expression during vascular remodeling in coronary artery disease and pulmonary arterial hypertension. Pharmacological and genetic inhibition of ACLY in human primary cultured VSMCs isolated from the coronary arteries of patients with coronary artery diseases and from the distal pulmonary arteries of patients with pulmonary arterial hypertension resulted in reduced cellular proliferation and migration and increased susceptibility to apoptosis. These cellular changes were linked to diminished glycolysis, reduced lipid synthesis, impairment in general control nonrepressed protein 5 (GCN5)-dependent histone acetylation and suppression of the transcription factor FOXM1. In vivo studies using a pharmacological inhibitor and VSMC-specific <i>Acly</i> knockout mice showed that ACLY inhibition alleviated vascular remodeling. ACLY inhibition alleviated remodeling in carotid injury and ligation models in rodents and attenuated pulmonary arterial hypertension in Sugen/hypoxia rat and mouse models. Moreover, ACLY inhibition showed improvements in vascular remodeling in human ex vivo models, which included cultured human coronary artery and saphenous vein rings as well as precision-cut lung slices. Our results propose ACLY as a novel therapeutic target for treating complex vascular diseases, offering promising avenues for future clinical intervention.