Abstract 209: ATIC-associated De Novo Purine Biosynthesis Is Critically Involved In Proliferative Arterial Disease

Abstract

Background: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis following angioplasty or stent placement. VSMCs reprogram their metabolisms to meet increased requirement of lipid, protein and nucleotide for their proliferation. D e novo purine biosynthesis is one of critical pathways for nucleotide synthesis. However, its role in proliferation of VSMCs in these arterial diseases has not been defined. Methods: De novo purine synthesis in proliferative VSMCs was evaluated by LC-MS/MS. The expression of ATIC/Atic (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last two steps of de novo purine biosynthesis pathway, was assessed in VMSCs of proliferative arterial neointima. Global and VSMC-specific knockout of Atic mice were generated and used for examining the role of Atic-associated purine metabolism in the formation of arterial neointima and atherosclerotic lesion. Results: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes including ATIC/Atic were observed in the neointima of the injured vessels and atherosclerotic lesions both in mouse and human. Global or specific knockout of Atic in VSMCs inhibited cell proliferation, attenuating the arterial neointima in models of mouse atherosclerosis and arterial restenosis. Conclusions: These results reveal that de novo purine biosynthesis plays an important role in VSMC proliferation in arterial disease. These findings suggest that targeting ATIC is a promising therapeutic approach to combat arterial diseases.