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首页> 外文期刊>Platelets >Dyslipidemia-associated atherogenic oxidized lipids induce platelet hyperactivity through phospholipase C gamma 2-dependent reactive oxygen species generation
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Dyslipidemia-associated atherogenic oxidized lipids induce platelet hyperactivity through phospholipase C gamma 2-dependent reactive oxygen species generation

机译：血脂血症相关的α-氧化脂质通过磷脂酶Cγ2依赖性活性氧物种诱导血小板多动

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摘要

Oxidized low-density lipoprotein (oxLDL) and associated oxidized phosphocholine-headgroup phospholipids (oxPCs) activate blood platelets through ligation of the scavenger receptor CD36. Previously, we found that oxLDL stimulated phosphorylation of phospholipase C gamma 2 (PLC gamma 2). However, the functional relevance of PLC gamma 2 phosphorylation in oxLDL-mediated platelet hyperactivity remained elusive. Here, we set out to explore the functional importance of PLC gamma 2 in oxLDL-mediated platelet activation using human and genetically modified murine platelets. The CD36-specific oxidized phospholipid (oxPC(CD36)) triggered the generation of reactive oxygen species (ROS) in platelets under static and arterial flow conditions. The ROS generation in response to oxPC(CD36) was sustained for up to 3 h but ablated in CD36- and PLC gamma 2-deficient platelets. The functional importance of ROS generation in response to atherogenic lipid stress was examined through measurement of P-selectin expression. OxPC(CD36) induced P-selectin expression, but required up to 60 min incubation, consistent with the timeline for ROS generation. P-selectin expression was not observed in CD36- and PLC gamma 2-deficient mice. The ability of oxPC(CD36) and oxLDL to stimulate P-selectin expression was prevented by incubation of platelets with the ROS scavenger N-acetyl-cysteine (NAC) and the NOX-2 inhibitor gp91ds-tat, but not with the NOX-1 inhibitor ML171. In summary, we provide evidence that prolonged exposure to oxLDL-associated oxidized phospholipids induces platelet activation via NOX-2-mediated ROS production in a CD36- and PLC gamma 2-dependent manner.
机译：通过连接清除剂CD36，氧化低密度脂蛋白（OXLD1）和相关的氧化磷酸化合物 - 头组磷脂（OXPCS）活化血小板。以前，我们发现oxldl刺激磷脂酶Cγ2（PLCγ2）的磷酸化。然而，牛油介导的血小板多动术中PLCγ2磷酸化的功能相关性仍然难以捉摸。在这里，我们首先使用人和遗传修饰的小鼠血小板探讨PLC介导的血小板活化中PLCγ2的功能重要性。 CD36特异性氧化磷脂（OXPC（CD36））在静态和动脉流动条件下引发了血小板中的活性氧物质（ROS）的产生。响应于OXPC（CD36）的ROS产生高达3小时但在CD36和PLCγ2缺陷血小板中烧蚀。通过测量p-SELIEN蛋白表达，检查了ROS产生响应致动血液应激的功能重要性。 OXPC（CD36）诱导p-选择蛋白表达，但最多需要60分钟孵育，与ROS生成的时间表一致。在CD36-和PLCγ2缺陷小鼠中未观察到p-选择蛋白表达。通过用ROS清除剂N-乙酰基半胱氨酸（NAC）和NOX-2抑制剂GP91DS-TAT，通过血小板孵育血小板来防止oxpc（cd36）和oxld1刺激p硒蛋白表达的能力，但没有用nox-1抑制剂ML171。总之，我们提供了延长暴露于oxldl相关的氧化磷脂的证据，诱导CD36-和PLCγ2依赖性NOx-2介导的ROS产生血小板活化。

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  • 来源
    《Platelets》 |2019年第4期|共6页
  • 作者

    Berger Martin; Wraith Katie; Woodward Casey; Aburima Ahmed; Raslan Zaher; Hindle Matthew S.; Moellmann Julia; Febbraio Maria; Naseem Khalid M.;

  • 作者单位

    Univ Hull Fac Hlth Sci Ctr Atherothrombosis &

    Metab Dis Hull York Med Sch Kingston Upon Hull N;

    Univ Hull Fac Hlth Sci Ctr Atherothrombosis &

    Metab Dis Hull York Med Sch Kingston Upon Hull N;

    Univ Hull Fac Hlth Sci Ctr Atherothrombosis &

    Metab Dis Hull York Med Sch Kingston Upon Hull N;

    Univ Hull Fac Hlth Sci Ctr Atherothrombosis &

    Metab Dis Hull York Med Sch Kingston Upon Hull N;

    Univ Leeds Leeds Inst Cardiovasc &

    Metab Med LIGHT Labs Leeds W Yorkshire England;

    Univ Leeds Leeds Inst Cardiovasc &

    Metab Med LIGHT Labs Leeds W Yorkshire England;

    Univ Hosp RWTH Aachen Dept Internal Med 1 D-52074 Aachen Germany;

    Univ Alberta Sch Dent Edmonton AB Canada;

    Univ Leeds Leeds Inst Cardiovasc &

    Metab Med LIGHT Labs Leeds W Yorkshire England;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 基础医学;
  • 关键词

    OxLDL; oxPC(CD36); platelet hyperactivity; PLC gamma 2; reactive oxygen species;

    机译：OXLDL;OXPC（CD36）;血小板多动;PLCγ2;活性氧物种;

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