Abdominal aortic aneurysm (AAA) is characterized by inflammatory cell infiltration and aggravated by hyperhomocysteinemia (HHcy). It is unknown whether the homocysteine (Hcy)-activated RNA methyltransferase NOP2/Sun domain family member 2 (NSun2) is associated with AAA. Here, we found that NSun2 deficiency significantly attenuated elastase-induced and HHcy-aggravated murine AAA with decreased T cell infiltration in the vessel walls. T cell labeling and adoptive transfer experiments confirmed that NSun2 deficiency inhibited the chemotaxis of vessels to T cells. RNA sequencing of endothelial cells showed that Hcy induced the accumulation of various metabolic enzymes of the phospholipid PC-LPC-LPA metabolic pathway, especially autotaxin (ATX). In the elastase-induced mouse model of AAA, ATX was specifically expressed in the endothelium and the plasma ATX concentration was upregulated and even higher in the HHcy group, which were decreased dramatically by NSun2 knockdown. In vitro Transwell experiments showed that ATX dose-dependently promoted T cell migration. HHcy may upregulate endothelial ATX expression and secretion and in turn recruit T cells into the vessel walls to induce vascular inflammation and consequently accelerate the pathogenesis of AAA. Mechanistically, secreted ATX interacted with T cells by binding to integrin α4, which subsequently activated downstream FAK/Src-RhoA signaling pathways and then induced T cell chemokinesis and adhesion. ATX overexpression in the vessel walls reversed the inhibited development of AAA in the NSun2-deficient mice. Therefore, NSun2 mediates the development of HHcy-aggravated AAA primarily by increasing endothelial ATX expression, secretion and T cell migration, which is a novel mechanism for HHcy-aggravated vascular inflammation and pathogenesis of AAA.

中文翻译：

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NSun2通过促进自分泌蛋白表达和T细胞募集来调节动脉瘤的形成。

腹主动脉瘤（AAA）的特征是炎性细胞浸润，高同型半胱氨酸血症（HHcy）加重。尚不清楚高半胱氨酸（Hcy）激活的RNA甲基转移酶NOP2 / Sun域家族成员2（NSun2）是否与AAA相关。在这里，我们发现NSun2缺乏显着减弱了弹性蛋白酶诱导的和HHcy加重的小鼠AAA，同时血管壁中的T细胞浸润减少。T细胞标记和过继转移实验证实NSun2缺乏抑制了血管对T细胞的趋化性。内皮细胞的RNA测序表明，Hcy诱导了磷脂PC-LPC-LPA代谢途径的各种代谢酶的积累，特别是自分泌运动因子（ATX）。在弹性蛋白酶诱导的AAA小鼠模型中，ATX在内皮中特异性表达，血浆ATX浓度上调，甚至在HHcy组中更高，而NSun2敲低显着降低了ATX浓度。体外Transwell实验表明，ATX剂量依赖性地促进T细胞迁移。HHcy可能上调内皮ATX的表达和分泌，进而募集T细胞进入血管壁以诱导血管炎症，从而加速AAA的发病机理。从机制上讲，分泌的ATX通过与整合素α4结合而与T细胞相互作用，后者随后激活下游的FAK / Src-RhoA信号传导途径，然后诱导T细胞趋化因子和粘附。血管壁中ATX的过表达逆转了NSun2缺陷小鼠中AAA的抑制发育。因此，