氧化脂促进LNK中的NETosis和动脉血栓形成 (SH2B3) 缺乏
Huijuan Dou1, Andriana Kotini2, Wenli Liu1
1Molecular Medicine, Columbia University Medical Center, New York (H.D., W.L., T.F., K.E.-U., T.X., S.A., M.Y., B.H., N.W., A.R.T.).
Circulation
|November 30, 2021
概括
造血性Lnk缺乏会促进中性粒细胞外陷 (NET) 的形成和动脉血栓形成. 针对氧化脂 (OxPL) 的疗法可能有利于具有特定遗传特征的冠状动脉疾病患者.
科学领域:
- 心血管生物学
- 免疫学
- 血液学
背景情况:
- LNK/SH2B3蛋白调节Janus激酶/信号转换器和转录激活器 (JAK/STAT) 的信号传输.
- 一种常见的LNK多态性 (R262W) 与中性恋,血栓细胞瘤和冠状动脉疾病有关.
- 在小鼠中,LNK缺乏导致血小板中性粒细胞聚集,动脉样硬化和血栓形成,这表明中性粒细胞外陷 (NETs) 的作用.
研究的目的:
- 研究血液形成性Lnk缺陷的小鼠在动脉样硬化和血栓形成中的NETs作用.
- 探索LNK缺陷促进NETosis的机制,其中包括氧化脂 (OxPL).
- 评估这些发现在具有特定基因突变的人群中的相关性.
主要方法:
- 具有Lnk和PAD4 (一种对NETosis必不可少的酶) 联合缺乏的繁殖小鼠.
- 将骨髓移植给Ldlr-/-小鼠,以评估动脉血症.
- 利用人类诱导的多能干细胞衍生细胞和英国生物库数据来证实人类的相关性和临床关联.
主要成果:
- 缺乏Lnk的小鼠表现出加速的血栓形成和NETosis,而PAD4缺陷使其逆转.
- 由氧化脂 (OxPL) 介导的Lnk缺乏血小板和中性粒细胞的相互作用和NETosis增加.
- 在Lnk缺陷小鼠中,针对OxPL的E06-scFv抗体片段逆转了NETosis,动脉样硬化和血栓形成. 人类研究证实了LNK(TT) 基因型的NETosis增加,并将LNK R262W等位基因与JAK2VF突变载体的冠状动脉疾病风险增加联系起来.
结论:
- 通过依赖OxPL的途径促进了NETosis和动脉血栓形成.
- 由于R262W变异而减少的LNK功能促进了NETosis,并增加了JAK2VF突变患者的冠状动脉疾病风险.
- 针对OxPL可能在特定的基因定型人群中为冠状动脉疾病提供治疗效益.
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