NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1
NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1
复制标题
DOI：
10.1161/circresaha.115.307674
复制
发表时间：
2016-03-18
影响因子：
20.1
通讯作者：
Wang, Xian
中科院分区：
文献类型：
--
作者：
Luo, Yuhong;Feng, Juan;Wang, Xian
基本原理：血管内皮炎症反应是血管疾病的重要环节，其中细胞间粘附分子1（ICAM-1）的表达是其重要组成部分。目的：探讨NOP 2/Sun结构域家族成员2（NSun 2）介导的mRNA甲基化对ICAM-1的调控机制，以及NSun 2-ICAM-1调控过程在血管炎症和移植物动脉硬化中的作用。通过使用体外，细胞内和体内甲基化测定，我们表明tRNA甲基转移酶NSun 2甲基化ICAM-1 mRNA。NSun 2的甲基化促进ICAM-1的翻译，从而增加白细胞与内皮细胞的粘附。肿瘤坏死因子或同型半胱氨酸通过抑制Aurora-B对NSun 2的磷酸化而激活NSun 2的甲基转移酶活性。在野生型大鼠中观察到的同型半胱氨酸处理的ICAM-1诱导水平和白细胞粘附至血管内皮的水平在NSun 2（-/-）大鼠中显著降低。结论：供体NSun 2通过甲基化ICAM-1 mRNA，上调ICAM-1的表达。这种调节过程影响血管炎症和同种异体移植物动脉硬化。
Rationale: Vascular endothelial inflammation, including the expression of intercellular adhesion molecule 1 (ICAM-1), is a key event in vascular diseases. However, the mechanisms underlying the regulation of ICAM-1 are largely unknown.Objective: To investigate the mechanisms on the regulation of ICAM-1 by NOP2/Sun domain family, member 2 (NSun2)-mediated mRNA methylation and the impact of NSun2-ICAM-1 regulatory process in vascular inflammation and allograft arteriosclerosis.Methods and Results: By using in vitro, in cells, and in vivo methylation assays, we showed that the tRNA methyltransferase NSun2 methylated the ICAM-1 mRNA. Methylation by NSun2 promoted the translation of ICAM-1, thereby increasing the adhesion of leukocytes to endothelial cells. Tumor necrosis factor- or homocysteine activated the methyltransferase activity of NSun2 by repressing the phosphorylation of NSun2 by Aurora-B. The levels of ICAM-1 induction and of leukocyte adhesion to vascular endothelium observed with homocysteine treatment in wild-type rats were markedly decreased in NSun2(-/-) rats. In a rat model of aortic allograft, the lack of donor NSun2 impaired the formation of allograft arteriosclerosis.Conclusions: NSun2 upregulates the expression of ICAM-1 by methylating ICAM-1 mRNA. This regulatory process impacts on vascular inflammation and allograft arteriosclerosis.