IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps.
IsoLGs (Isolevuglandins) Drive Neutrophil Migration in Hypertension and Are Essential for the Formation of Neutrophil Extracellular Traps.
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DOI：
10.1161/hypertensionaha.122.19305
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发表时间：
2022-08
期刊：
影响因子：
8.3
通讯作者：
Patrick, David M.
中科院分区：
文献类型：
--
作者：
Krishnan, Jaya;de la Visitacion, Nestor;Hennen, Elizabeth M.;Amarnath, Venkataraman;Harrison, David G.;Patrick, David M.
异丙肾上腺素(Isolevuglandins，IsoLGs)是在活性氧(ROS)存在下，脂质过氧化形成的亲电产物。IsoLGs通过一种未知的机制导致高血压。研究表明，ROS的产生推动了中性粒细胞胞外陷阱(NETs)的形成，NETs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等密度脂蛋白在高血压中性粒细胞迁移和网状形成(NETsis)中的作用。用血管紧张素II(Ang II)和特异性同功酶清除剂2-羟基苯甲胺(2HOBA)处理小鼠，用单细胞测序和流式细胞术检测组织中性粒细胞和净蓄积。用免疫荧光和活细胞共聚焦显微镜研究分离的人中性粒细胞，以确定isLGs在NET病和中性粒细胞染色质扩张中的作用。对Sham、Ang II和Ang II+2HOBA处理的小鼠进行的单细胞测序显示，中性粒细胞是2HOBA的主要靶点。2HOBA治疗可阻断外周中性粒细胞迁移、主动脉净积聚和肾净积聚。在分离的人中性粒细胞中，等LGs在NET代谢过程中积聚，清除等LGs可预防NETsis。IsoLGs在网织红细胞分裂过程中驱动中性粒细胞染色质扩张，并破坏核小体结构。这些观察确定了等LGs在中性粒细胞迁移和高血压的NETsis中的关键作用，并提供了一种潜在的治疗Net相关疾病的方法，包括高血压和相关的末端器官损伤。
Isolevuglandins (IsoLGs) are electrophilic products of lipid peroxidation formed in the presence of reactive oxygen species (ROS). IsoLGs contribute to hypertension by an unknown mechanism. Studies have shown that ROS 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. Mice were treated with Angiotensin II (Ang II) and the specific isoLG scavenger 2-hydroxybenzylamine (2HOBA) 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. Single cell sequencing performed on sham, Ang II, and Ang II + 2HOBA treated mice revealed neutrophils as a primary target of 2HOBA. Peripheral neutrophil migration, aortic NET accumulation, and renal NET accumulation is blocked with 2HOBA 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. 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.