高同型半胱氨酸血症放大高脂引起动脉粥样硬化早期发病--管周脂肪的抗原呈递作用

Hyperhomocysteinmia (HHcy) is a novel independent risk factor of atherosclerosis pathogenesis. Epidemiological studies show that HHcy patients associated with obesity or insulin resistance develop atherosclerosis much earlier. However, the underlying mechanism is unclear. Our study indicates that: feed ApoE-/- mice with high homocysteine (Hcy) plus high-fat diet for 2 weeks induces antigen presenting function of perivascular and abdominal adipocytes; enhances the interaction between adipocytes and inflammatory T cells; augments the production and secretion of the free fatty acids. Thus, this study is to reveal antigen presenting function of perivascular or/and abdominal adipocytes might be one of the most important initiated mechanisms of HHcy amplified early pathogenesis of high-fat diet-induced atherosclerosis. This study will focus on: 1. Using MHC-II-/- atherosclerosis mouse model (in vivo) and coculture of adipocytes and T cells (in vitro), we will uncover Hcy or/and free fatty acids are involved in T cell activation by antigen presenting effect from perivascular and other source adipocytes; the T cell activation further enhances antigen presenting effect of adipocytes; and those mechanisms. 2. We will perform high throughput lipidomics technique to clarify interaction and the mechanisms of Hcy with free fatty acid metabolism. Our study will uncover the status and function of antigen presenting effect from perivascular adipose tissue in HHcy amplified early inflammatory pathogenesis of high-fat diet-induced atherosclerosis.

高同型半胱氨酸血症（HHcy）是动脉粥样硬化发病的独立危险因子。流行病研究显示HHcy伴发肥胖易早发动脉粥样硬化，但关联机制不清。我们研究显示：ApoE-/-小鼠喂养同型半胱氨酸（Hcy）加高脂2周即在血管管周和腹部脂肪细胞中诱导出抗原呈递功能，与致炎T细胞相互作用增加，游离脂肪酸生成和释放增加。本研究将揭示管周或/和外周脂肪细胞的抗原呈递功能可能是HHcy放大高脂饮食引起动脉粥样硬化早期发病的始动机制之一。重点研究：1. 通过整体MHC-II-/-的动脉粥样硬化小鼠和离体脂肪和T细胞共培养揭示Hcy或/和游离脂肪酸协同作用参与管周等不同部位脂肪细胞源的抗原呈递作用下T细胞激活而放大脂肪细胞抗原呈递的作用及机制。2. 利用高通量脂质代谢组学技术初步搞清Hcy与游离脂肪酸代谢途径的相互作用及机制，以揭示管周脂肪的抗原呈递作用在HHcy放大高脂引起动脉粥样硬化早期炎症免疫发病中的地位和作用。

本项目主要研究了血管的管周脂肪或/和外周脂肪细胞的抗原呈递功能，从而激活T细胞和加速血管炎症，参与高同型半胱氨酸血症(HHcy)引起的动脉粥样硬化发生和发展的机制。揭示：(1)HHcy引起脂肪细胞HIF1α-PLA2依赖的与巨噬细胞相互作用促进炎性小体生成,而多肽ADM2-HIF2α通过促进脂质利用抑制脂肪组织胰岛素抵抗和动脉粥样硬化发病；(2）HHcy促进脂肪细胞MHC-II表达和抗原提呈功能，因此激活脂肪组织T细胞；（3）HHcy促进白细胞与血管内皮粘附增加; 还直接引起T细胞和B细胞炎性激活的代谢重塑新机制；（4）HHcy引起B淋巴细胞分泌特异的抗β2磷脂结合蛋白I抗体，放大动脉瘤的发病。在本项目资助下基本上完成了原计划研究内容，取得了一些具有自主知识产权的研究结果，已经发表SCI论文14篇，另外还发表3篇综述。也培养了研究团队。这些成果不仅使我们认识了代谢和免疫介导血管疾病发病新机制，也为筛选早期诊断提供了新思路和新靶点。