Background:IsoLGs (isolevuglandins) are electrophilic products of lipid peroxidation formed in the presence of reactive oxygen species. IsoLGs contribute to hypertension by an unknown mechanism. Studies have shown that reactive oxygen species production drives the formation of neutrophil extracellular traps (NETs) and that NETs accumulate within the aorta and kidneys of patients with hypertension. The purpose of this study was to determine the role of isoLGs in neutrophil migration and NET formation (NETosis) in hypertension.Methods:Mice were treated with Ang II (angiotensin II) and the specific isoLG scavenger 2-hydroxybenzylamine and examined for tissue neutrophil and NET accumulation by single-cell sequencing and flow cytometry. Isolated human neutrophils were studied to determine the role of isoLGs in NETosis and neutrophil chromatin expansion by immunofluorescence and live cell confocal microscopy.Results:Single-cell sequencing performed on sham, Ang II, and Ang II+2-hydroxybenzylamine treated mice revealed neutrophils as a primary target of 2-hydroxybenzylamine. Peripheral neutrophil migration, aortic NET accumulation, and renal NET accumulation is blocked with 2-hydroxybenzylamine treatment. In isolated human neutrophils, isoLGs accumulate during NETosis and scavenging of isoLGs prevents NETosis. IsoLGs drive neutrophil chromatin expansion during NETosis and disrupt nucleosome structure.Conclusions:These observations identified a critical role of isoLGs in neutrophil migration and NETosis in hypertension and provide a potential therapy for NET-associated diseases including hypertension and associated end organ damage.

中文翻译：

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IsoLG（Isolevuglandins）在高血压中驱动中性粒细胞迁移，对于中性粒细胞胞外陷阱的形成至关重要

背景：IsoLG（isolevuglandins）是在活性氧存在下形成的脂质过氧化的亲电产物。IsoLGs 通过未知的机制导致高血压。研究表明，活性氧的产生会促进中性粒细胞胞外陷阱 (NET) 的形成，并且 NET 在高血压患者的主动脉和肾脏内积聚。本研究的目的是确定 isoLG 在高血压中性粒细胞迁移和 NET 形成 (NETosis) 中的作用。方法：用 Ang II（血管紧张素 II）和特异性 isoLG 清除剂 2-羟基苄胺治疗小鼠，并检查组织中性粒细胞和 NET 形成（NETosis）。通过单细胞测序和流式细胞术检测 NET 积累。研究分离的人中性粒细胞，通过免疫荧光和活细胞共聚焦显微镜确定 isoLG 在 NETosis 和中性粒细胞染色质扩增中的作用。结果：对假手术、Ang II 和 Ang II+2-羟基苄胺处理的小鼠进行的单细胞测序显示，中性粒细胞为2-羟基苄胺的主要目标。2-羟基苄胺治疗可阻断外周中性粒细胞迁移、主动脉 NET 积累和肾脏 NET 积累。在分离的人类中性粒细胞中，isoLG 在 NETosis 期间积累，并且 isoLG 的清除可防止 NETosis。IsoLG 在 NETosis 期间驱动中性粒细胞染色质扩张并破坏核小体结构。结论：这些观察结果确定了 isoLG 在中性粒细胞迁移和高血压中的 NETosis 中发挥着关键作用，并为 NET 相关疾病（包括高血压和相关终末器官损伤）提供了潜在的治疗方法。