机构：[1]State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, China[2]Vascular Biology Center,Medical College of Georgia, Augusta University.[3]Department of Cardiovascular Surgery, Peking University Shenzhen Hospital, China北京大学深圳医院深圳市康宁医院深圳医学信息中心[4]Huck Institutes of the Life Sciences ,Pennsylvania State University, University Park.[5]Department of Pharmacology and Toxicology,Medical College of Georgia, Augusta University.[6]Department of Cellular Biology and Anatomy,Medical College of Georgia, Augusta University.[7]Department of Medicine, Vanderbilt University, Nashville, TN[8]Department of Neuroscience & Regenerative Medicine,Medical College of Georgia, Augusta University.[9]Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China[10]Department of Chemistry, Pennsylvania State University, University Park[11]Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA[12]Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL[13]Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL
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.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.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.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.
基金：
National Science Foundation
of China (82070461); Shenzhen Science and Technology Innovation Committee
(GXWD20201231165807007-20200818123312001); Shenzhen-Hong
Kong Institute of Brain Science–Shenzhen Fundamental Research Institutions
(2019SHIBS0004); American Heart Association (19TPA34910043); and National
Institutes of Health (R35CA197459, P01 CA120964, R01HL142097,
R01EY030500, R01EY033369, R01EY033737, and R01GM024129).
第一作者机构：[1]State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, China[2]Vascular Biology Center,Medical College of Georgia, Augusta University.
通讯作者：
通讯机构：[2]Vascular Biology Center,Medical College of Georgia, Augusta University.[6]Department of Cellular Biology and Anatomy,Medical College of Georgia, Augusta University.[*1]Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, 1459 Laney Walker Boulevard, Augusta, GA 30912
推荐引用方式(GB/T 7714)：
Ma Qian,Yang Qiuhua,Xu Jiean,et al.ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease[J].CIRCULATION.2022,146(19):1444-1460.doi:10.1161/CIRCULATIONAHA.121.058901.
APA：
Ma Qian,Yang Qiuhua,Xu Jiean,Zhang Xiaoyu,Kim David...&Huo Yuqing.(2022).ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease.CIRCULATION,146,(19)
MLA：
Ma Qian,et al."ATIC-Associated De Novo Purine Synthesis Is Critically Involved in Proliferative Arterial Disease".CIRCULATION 146..19(2022):1444-1460
医学