高同型半胱氨酸血症促进动脉粥样硬化早期发病炎症新机制——tRNA甲基转移酶NSun2的调控作用

The interaction between the endothelial and immune cells is an early event in hyperhomocysteinemia (HHcy)-induced vascular injury and atherosclerosis. In our previous work of the Youth Fund Project, we have demonstrated that CTLA-4 endocytosis mediates HHcy-induced T cell activation followed by upregulated expression of LFA-1, and promotes these cells to roll and adhere onto the endothelium. As the LFA-1 receptor, upregulation of endothelial ICAM-1, might play a key role in the T cell-endothelial cell interaction and HHcy-accelerated atherosclerosis. Results of preliminary experiments have also shown that HHcy increased the expression of NSun2 and ICAM-1; NSun2 could bind to and methylate ICAM-1 3’-UTR, thus increased the ICAM-1 expression by enhancing its translation; Knockdown of NSun2 decreased endothelial ICAM-1 expression and the number of adhered cells. This project will explore the role of NSun2-ICAM-1 axis in HHcy-accelerated atherosclerosis. Our study will provide a new mechanism for HHcy-related inflammation from the angle of RNA methylation.

内皮与免疫细胞交互作用是高同型半胱氨酸血症(HHcy)致血管炎症损伤而促进动脉粥样硬化的早期事件。申请者青年基金揭示细胞膜CTLA-4分子内化介导HHcy引起的T细胞激活,继而粘附分子LFA-1表达增加,促进其在血管内皮滚动粘附。LFA-1受体,即内皮粘附分子ICAM-1表达也增加。预实验表明:Hcy上调tRNA甲基转移酶NSun2;NSun2结合并甲基化ICAM-1 3’UTR而增加ICAM-1蛋白表达;敲低NSun2致内皮ICAM-1表达降低,与之粘附的免疫细胞减少。由此假设HHcy上调NSun2表达后结合并甲基化ICAM-1 3’UTR,上调内皮ICAM-1蛋白表达,增加内皮细胞与免疫细胞相互作用,促进动脉粥样硬化早期发病。本项目将在细胞和整体动物水平上,探讨NSun2介导HHcy上调内皮ICAM-1表达的分子机制及意义,从RNA甲基化修饰角度解析HHcy促进动脉粥样硬化发病新机理。

内皮与免疫细胞交互作用是高同型半胱氨酸血症(HHcy)致血管炎症损伤而促进动脉粥样硬化的早期事件。本项目主要阐明NSun2 调控ICAM-1 的翻译并揭示其作用的具体分子机制；证实血管内皮细胞NSun2-ICAM-1 加速其对血液中白细胞的滚动、粘附，最终促进HHcy引起动脉粥样硬化的提前发生；除此之外，本研究项目有了新的发现：淋巴细胞内糖脂代谢紊乱引起细胞过度激活，继而通过与血管内皮细胞相互作用，也参与了HHcy加速动脉粥样硬化发生发展的早期病理过程。

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