ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease

Qian Ma, Qiuhua Yang, Jiean Xu, Xiaoyu Zhang, David Kim, Zhiping Liu, Qingen Da, Xiaoxiao Mao, Yaqi Zhou, Yongfeng Cai, Vidhi Pareek, Ha Won Kim, Guangyu Wu, Zheng Dong, Wen Liang Song, Lin Gan, Chunxiang Zhang, Mei Hong, Stephen J. Benkovic, Neal L. WeintraubDavid Fulton, John M. Asara, Issam Ben-Sahra, Yuqing Huo

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Background: Proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of arterial diseases, especially in arterial restenosis after angioplasty or stent placement. VSMCs reprogram their metabolism to meet the increased requirements of lipids, proteins, and nucleotides for their proliferation. De novo purine synthesis 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 liquid chromatography-tandem mass spectrometry. The expression of ATIC (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase), the critical bifunctional enzyme in the last 2 steps of the de novo purine synthesis pathway, was assessed in VSMCs 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 lesions. Results: In this study, we found that de novo purine synthesis was increased in proliferative VSMCs. Upregulated purine synthesis genes, including ATIC, were observed in the neointima of the injured vessels and atherosclerotic lesions both in mice and humans. 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 synthesis 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.

Original languageEnglish (US)
Pages (from-to)1444-1460
Number of pages17
JournalCirculation
Volume146
Issue number19
DOIs
StatePublished - Nov 8 2022

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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