ATP Citrate Lyase Drives Vascular Remodeling Diseases Development Through Metabolic-Epigenetic Reprograming.
Our study explores the previously uncharted role of ATP-citrate lyase (ACLY) in vascular remodeling within the pulmonary and coronary circulations, providing novel insights into the pathogenesis of pulmonary hypertension and coronary artery diseases. ACLY, known for its involvement in de novo lipid synthesis and histone acetylation, emerges as a key regulator in sustaining vascular smooth muscle cell proliferation and survival. Utilizing rare human coronary and pulmonary artery tissues, our findings reveal an upregulation of ACLY expression during vascular remodeling processes. Inhibition of ACLY, achieved through pharmacological and molecular interventions in humans primary cultured vascular smooth muscle cells, leads to decreased proliferation, migration, and resistance to apoptosis. Mechanistically, these effects are associated with diminished glycolysis, lipid synthesis, GCN5-dependent histone acetylation, and FOXM1 activation. In vivo experiments, combining pharmacological and VSMC-specific ACLY knockout mice, ACLY inhibition demonstrate its efficacy in mitigating systemic vascular remodeling and reducing pulmonary hypertension. Notably, initiating ACLY inhibition post-disease onset reverses pathological conditions, positioning ACLY as a promising therapeutic target. Human ex-vivo tissue culture further supports our findings, showcasing reduced vascular remodeling in cultured human coronary artery rings and a reversal of pulmonary artery remodeling in precision-cut lung slices upon ACLY inhibition. This study introduces a groundbreaking concept, linking disparate abnormalities in vascular diseases to a common pathogenetic denominator, ACLY. The identified "multiple-hit" therapeutic approach presents potential targets for addressing complex vascular diseases, offering avenues for future clinical interventions. Overall design: Our study delineates the pivotal role of ATP-citrate lyase in pulmonary hypertension and coronary artery diseases.