血管平滑肌细胞(VSMC)的增殖是动脉疾病的标志,尤其是血管成形术或支架置入后的动脉再狭窄。VSMC重新编程它们的代谢以满足增加的脂质需求,蛋白质,和核苷酸的增殖。从头嘌呤合成是核苷酸合成的关键途径之一。然而,其在这些动脉疾病中VSMC增殖中的作用尚未确定。
通过液相色谱-串联质谱法评估增殖性VSMC中的从头嘌呤合成。ATIC(5-氨基咪唑-4-甲酰胺核糖核苷酸甲酰基转移酶/肌苷一磷酸环水解酶)的表达,从头嘌呤合成途径最后两步中的关键双功能酶,在增生性动脉新内膜的VSMC中进行评估。产生Atic小鼠的全局和VSMC特异性敲除,并用于检查ATIC相关嘌呤代谢在动脉新内膜和动脉粥样硬化病变形成中的作用。
在这项研究中,我们发现在增殖性VSMC中嘌呤从头合成增加。嘌呤合成上调基因,包括ATIC,在小鼠和人类的受伤血管和动脉粥样硬化病变的新内膜中观察到。VSMC中Atic的全局或特异性敲除抑制细胞增殖,在小鼠动脉粥样硬化和动脉再狭窄模型中减弱动脉新生内膜。
这些结果表明嘌呤从头合成在动脉疾病的VSMC增殖中起重要作用。这些发现表明靶向ATIC是对抗动脉疾病的有希望的治疗方法。
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.