Aims Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that induces a reversible post-translational modification (ISGylation) and can also be secreted as a free form. ISG15 plays an essential role as host-defence response to microbial infection; however, its contribution to vascular damage associated with hypertension is unknown. Methods and results Bioinformatics identified ISG15 as a mediator of hypertension-associated vascular damage. ISG15 expression positively correlated with systolic and diastolic blood pressure and carotid intima-media thickness in human peripheral blood mononuclear cells. Consistently, Isg15 expression was enhanced in aorta from hypertension models and in angiotensin II (AngII)-treated vascular cells and macrophages. Proteomics revealed differential expression of proteins implicated in cardiovascular function, extracellular matrix and remodelling, and vascular redox state in aorta from AngII-infused ISG15–/– mice. Moreover, ISG15–/– mice were protected against AngII-induced hypertension, vascular stiffness, elastin remodelling, endothelial dysfunction, and expression of inflammatory and oxidative stress markers. Conversely, mice with excessive ISGylation (USP18C61A) show enhanced AngII-induced hypertension, vascular fibrosis, inflammation and reactive oxygen species (ROS) generation along with elastin breaks, aortic dilation, and rupture. Accordingly, human and murine abdominal aortic aneurysms showed augmented ISG15 expression. Mechanistically, ISG15 induces vascular ROS production, while antioxidant treatment prevented ISG15-induced endothelial dysfunction and vascular remodelling. Conclusion ISG15 is a novel mediator of vascular damage in hypertension through oxidative stress and inflammation.

中文翻译：

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干扰素刺激基因 15 通路是血管紧张素 II 输注小鼠通过增加氧化应激导致内皮功能障碍和动脉瘤发展的新型介质

目的 干扰素刺激基因 15 (ISG15) 编码一种泛素样蛋白，可诱导可逆的翻译后修饰 (ISGylation)，也可以以游离形式分泌。ISG15 在宿主对微生物感染的防御反应中起着至关重要的作用；然而，它对与高血压相关的血管损伤的贡献尚不清楚。方法和结果 生物信息学将 ISG15 鉴定为高血压相关血管损伤的介质。ISG15 表达与人外周血单核细胞的收缩压和舒张压以及颈动脉内膜中层厚度呈正相关。一致地，Isg15 表达在来自高血压模型的主动脉和血管紧张素 II (AngII) 处理的血管细胞和巨噬细胞中增强。蛋白质组学揭示了在注入 AngII 的 ISG15–/– 小鼠的主动脉中涉及心血管功能、细胞外基质和重塑以及血管氧化还原状态的蛋白质的差异表达。此外，ISG15–/– 小鼠免受 AngII 诱导的高血压、血管僵硬、弹性蛋白重塑、内皮功能障碍以及炎症和氧化应激标志物的表达。相反，过度 ISGylation (USP18C61A) 的小鼠表现出增强的 AngII 诱导的高血压、血管纤维化、炎症和活性氧 (ROS) 生成以及弹性蛋白断裂、主动脉扩张和破裂。因此，人和小鼠腹主动脉瘤显示出增强的 ISG15 表达。从机制上讲，ISG15 诱导血管 ROS 的产生，而抗氧化剂治疗可防止 ISG15 诱导的内皮功能障碍和血管重塑。结论 ISG15 是一种通过氧化应激和炎症介导高血压血管损伤的新型介质。