Abstract 11858: ATIC-Mediated De Novo Purine Synthesis Protects Endothelial Cells From Disturbed Flow-Induced Injury in Atherosclerosis

Abstract

Aims: Disturbed flow at arterial bifurcations and curvatures of blood vessels, combining with other atherosclerotic risk factors, promotes endothelial cell (EC) DNA damage and the subsequent EC death, compromises the integrity of the endothelial barrier and ultimately leads to the formation of atherosclerotic lesions. ECs reprogram their metabolism to protect them from atherogenic injury induced by disturbed flow. De novo purine synthesis (DNPS) has been reported to regulate DNA repair and cell proliferation in cancer cells, however, its role in atherosclerosis has not been determined. 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC) is the enzyme that catalyzes last two steps of DNPS. We investigated the role of ATIC-driven DNPS in flow-induced EC metabolic reprogramming and in the development of atherosclerosis. Methods and Results: The expression of DNPS and DNA damage associated genes in ECs exposed to disturbed flow were assessed by analyzing the published RNA-Seq datasets. ATIC protein expression and DNA damage were examined in the endothelium at atheroprone regions of mouse aortas. Mice with EC-specific Atic knockout were utilized to investigate the role of endothelial ATIC in atherosclerosis. ATIC-mediated DNPS were increased in ECs exposed to disturbed flow both in vitro and in vivo , which was highly associated with the increased DNA damage response. EC-specific Atic knockout enhanced DNA damage of ECs, EC apoptosis, EC permeability and the subsequent formation of atherosclerotic lesions. Conclusion: Enhanced ATIC-mediated DNPS in ECs exposed to disturbed flow supplies purine nucleotides to repair DNA damage and to preserve EC barrier integrity in vulnerable atheroprone regions, and ultimately protects against the development and progression of atherosclerosis.