Platelet protein disulfide isomerase is required for thrombus formation but not for hemostasis in mice
Platelet protein disulfide isomerase is required for thrombus formation but not for hemostasis in mice
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DOI：
10.1182/blood-2013-03-492504
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发表时间：
2013-08-08
期刊：
影响因子：
20.3
通讯作者：
Cho, Jaehyung
中科院分区：
文献类型：
--
作者：
Kim, Kyungho;Hahm, Eunsil;Cho, Jaehyung
来自血管内细胞的蛋白二硫异构酶（PDI）是血栓形成所必需的。然而，血小板PDI是否与该过程有关尚不清楚。使用血小板特异性pdi缺陷小鼠，我们证明pdi缺失的血小板在凝血酶、胶原蛋白和二磷酸腺苷诱导下具有聚集和三磷酸腺苷分泌缺陷。野生型PDI挽救了这些缺陷，而突变型PDI却没有，这表明血小板表面PDI的异构酶活性对调控作用至关重要。pdi缺陷的血小板表达细胞内内质网蛋白57 （ERp57）和ERp72水平升高。血小板PDI调节α (IIb) β(3)整合素激活，但不调节p -选择素暴露、Ca2+动员、β (3)-talin1相互作用或血小板在固定纤维蛋白原上的扩散。ERp57的抑制进一步降低了α (IIb) β(3)整合素的激活和活化的PDI缺陷血小板的聚集，提示PDI和ERp57在血小板功能中的不同作用。我们发现血小板PDI对剪切作用下胶原包被表面的血栓形成很重要。活体显微镜显示，血小板PDI对血小板聚集很重要，但对激光诱导的小动脉损伤后的初始粘附和纤维蛋白生成并不重要。血小板特异性pdi缺陷小鼠尾出血时间无明显增加。我们的结果提供了重要的证据，血小板PDI是必不可少的血栓形成，而不是止血小鼠。
Protein disulfide isomerase (PDI) derived from intravascular cells is required for thrombus formation. However, it remains unclear whether platelet PDI contributes to the process. Using platelet-specific PDI-deficient mice, we demonstrate that PDI-null platelets have defects in aggregation and adenosine triphosphate secretion induced by thrombin, collagen, and adenosine diphosphate. Such defects were rescued by wildtype but not mutant PDI, indicating that the isomerase activity of platelet surface PDI is critical for the regulatory effect. PDI-deficient platelets expressed increased levels of intracellular ER protein 57 (ERp57) and ERp72. Platelet PDI regulated alpha(IIb)beta(3) integrin activation but not P-selectin exposure, Ca2+ mobilization, beta(3)-talin1 interaction, or platelet spreading on immobilized fibrinogen. Inhibition of ERp57 further diminished alpha(IIb)beta(3) integrin activation and aggregation of activated PDI-deficient platelets, suggesting distinct roles of PDI and ERp57 in platelet functions. We found that platelet PDI is important for thrombus formation on collagen-coated surfaces under shear. Intravital microscopy demonstrates that platelet PDI is important for platelet accumulation but not initial adhesion and fibrin generation following laser-induced arteriolar injury. Tail bleeding time in platelet-specific PDI-deficient mice were not significantly increased. Our results provide important evidence that platelet PDI is essential for thrombus formation but not for hemostasis in mice.