Defective Association of the Platelet Glycoprotein Ib-IX Complex with the Glycosphingolipid-Enriched Membrane Domain Inhibits Murine Thrombus and Atheroma Formation.
Defective Association of the Platelet Glycoprotein Ib-IX Complex with the Glycosphingolipid-Enriched Membrane Domain Inhibits Murine Thrombus and Atheroma Formation.
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DOI：
10.4049/jimmunol.1501946
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发表时间：
2016-07-01
期刊：
影响因子：
--
通讯作者：
Peng Y
中科院分区：
文献类型：
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作者：
Zhou H;Ran Y;Da Q;Shaw TS;Shang D;Reddy AK;López JA;Ballantyne CM;Ware J;Wu H;Peng Y
血小板糖蛋白Ib-IX复合物定位于膜脂质结构域对于血小板粘附于血管性血友病因子（vWf）和随后的体外血小板活化是必不可少的。然而，这种定位在体内的重要性从未得到解决。我们最近发现Ibα和Ibβ之间的二硫键对于Ibα与鞘糖脂富集膜（GEM）结构域的结合至关重要，在本研究中，我们建立了表达这种突变型人Ibα的转基因小鼠模型，该突变型人Ibα也缺乏内源性Ibα（HαSSMα−/−）。该模型的表征表明Ibα从鼠血小板GEM中的解离与CHO细胞中表达的相似，这与转基因血小板与vWf离体和体内粘附受损密切相关。此外，我们将我们的转基因小鼠培育成动脉粥样硬化易感背景（HαSSMα−/−ApoE−/−和HαWTMα−/−ApoE−/−）。我们观察到，动脉粥样硬化的形成显着抑制突变小鼠，血小板结合的CD 11 c+白细胞循环（CD 45 +/CD 11 c +/CD 41+）和居住在动脉粥样硬化病变（CD 45 +/CD 11 c+），表明血小板介导的粘附和浸润的CD 11 c+白细胞可能是机制之一。这些观察结果提供了第一个体内证据，表明膜GEM在GP Ib-IX复合物的功能中是生理和病理生理关键的。
Localization of the platelet glycoprotein Ib-IX complex to the membrane lipid domain is essential for platelet adhesion to von Willebrand factor (vWf) and subsequent platelet activation in vitro. Yet, the in vivo importance of this localization has never been addressed. We recently found that the disulfide linkage between Ibα and Ibβ is critical for the association of Ibα with the glycosphingolipid-enriched membrane (GEM) domain, in this study, we established a transgenic mouse model expressing this mutant human Ibα that is also devoid of endogenous Ibα (HαSSMα−/−). Characterization of this model demonstrated a similar dissociation of Ibα from murine platelet GEMs to that expressed in CHO cells, which correlates well with the impaired adhesion of the transgenic platelets to vWf ex vivo and in vivo. Furthermore, we bred our transgenic mice into an atherosclerosis-prone background (HαSSMα−/−ApoE−/− and HαWTMα−/−ApoE−/−). We observed that atheroma formation was significantly inhibited in mutant mice where fewer platelet-bound CD11c+ leukocytes were circulating (CD45+/CD11c+/CD41+) and residing in atherosclerotic lesions (CD45+/CD11c+), suggesting that platelet-mediated adhesion and infiltration of CD11c+ leukocytes may be one of the mechanisms. These observations provide the first in vivo evidence showing that the membrane GEMs is physiologically and pathophysiologically critical in the function of the GP Ib-IX complex.