Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo
Platelet GPVI binds to collagenous structures in the core region of human atheromatous plaque and is critical for atheroprogression in vivo
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DOI：
10.1007/s00395-008-0722-3
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发表时间：
2008-06-01
影响因子：
9.5
通讯作者：
Gawaz, Meinrad
中科院分区：
文献类型：
--
作者：
Schulz, Christian;Penz, Sandra;Gawaz, Meinrad
血小板粘附于动脉粥样硬化血管壁诱导血栓形成，并促进血管炎症和动脉粥样硬化进展。在本研究中，我们研究了血小板胶原受体糖蛋白（GP）VI与人动脉粥样硬化斑块（AP）的结合以及GPVI介导的血小板粘附在动脉粥样硬化进展中的作用。可溶性GPVI-Fc融合蛋白与固定的I型胶原、III型胶原结合，并且主要与人颈动脉粥样硬化斑块的核心区域结合。GPVI-Fc结合的模式类似于III型胶原的免疫染色模式，并且不同于I型胶原的免疫染色，其在帽中比在核心中更强烈。抗GPVI单克隆抗体5C 4或用抗I型胶原和抗III型胶原抗体或GPVI-Fc预处理斑块，可抑制搅拌血液中斑块诱导的血小板聚集和流动下血小板粘附/聚集体形成。然而，GPVI-Fc结合与单个斑块的血小板聚集活性之间没有相关性。通过小动物正电子发射断层扫描（PET）评估，GPVI也与ApoE缺陷小鼠体内动脉粥样硬化动脉结合。长期给予可溶性GPVI可减弱ApoE缺陷小鼠的动脉粥样硬化进展。在人类中，GPVI与斑块核心区域的I型和III型胶原结构结合介导斑块诱导的血小板粘附和聚集，但GPVI结合不是斑块的唯一血小板活化决定因素。在小鼠中，GPVI介导的血小板粘附于动脉粥样硬化血管壁参与了体内动脉粥样硬化的进展。综上所述，我们的数据表明GPVI是预防动脉粥样硬化血栓形成事件和动脉粥样硬化进展的相关靶点。
Platelet adhesion to the atherosclerotic vascular wall induces thrombosis and boosters vascular inflammation and atheroprogression. In the present study we studied the binding of the platelet collagen receptor glycoprotein (GP) VI to human atherosclerotic plaques (AP) and the role of GPVI-mediated platelet adhesion for atheroprogression. Soluble GPVI-Fc fusion protein bound to immobilized collagen type I, collagen type III, and predominantly to the core region of human carotid atheromatous plaques. The pattern of GPVI-Fc binding was similar to the immunostaining pattern of collagen type III and differed from the immunostaining of collagen type I, which was more intense in the cap than in the core. Plaque-induced platelet aggregation in stirred blood and platelet adhesion/aggregate formation under flow were inhibited by the anti-GPVI monoclonal antibody 5C4 or by pretreatment of plaques with anti-collagen type I and anti-collagen type III antibody, or GPVI-Fc. However, there was no correlation between GPVI-Fc binding and platelet aggregating activity of individual plaques. GPVI bound also to atherosclerotic arteries of ApoE-deficient mice in vivo as assessed by small animal positron emission tomography (PET). Prolonged administration of soluble GPVI attenuated atheroprogression in ApoE-deficient mice. In humans, GPVI binding to collagenous type I and type III structures of the plaque core region mediates plaque-induced platelet adhesion and aggregation, but GPVI binding is not the sole platelet-activating determinant of plaques. In mice, GPVI-mediated platelet adhesion to the atherosclerotic vascular wall is involved in atheroprogression in vivo. Taken together, our data suggests that GPVI is a relevant target to prevent atherothrombotic events and atheroprogression.