Mechanism of platelet activation by Helicobacter Pylori

幽门螺杆菌激活血小板的机制

• 批准号: 16590449
• 负责人: ASAZUMA Naoki
• 金额: $ 2.24万
• 依托单位: University of Yamanashi
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590449/
• 关键词: platelets; Helicobacter Pylori; VacA; GPIb; von Willebrand factor; GEMs; platelet aggregation; platelet activation; ヘリコバクター・ピロリ; VWF

Idiopatic thrombocytopenic purpura (ITP), a disorder characterized by autoantibody-mediated platelet destruction, may be primary or seconday to various illness including lymphoproliferative autoimmune, or infectious diseases. There are increasing data on the association between Helicobacter pylori infection and idipatic thrombocytopenic purupura and the significant increase of in platelet count after bacterial eradication. These results suggest that Helicobacter pyroli infection induces platelet activation in thrombus formation. The aim of this study is to consider the mechanism of platelet activation induced by VacA, Helicobacter pylori vacuolating cytotoxin. Platelet adhesion to subendothelial structure is an early and critical event in hemostasis and thrombosis. von Willebrand factor (VWF) is a major adhesive glycoprotein (GP) required for normal hemostasis under condition of high shear stress, such as those that occur in small arterioles and arterial capillaries. In the presence of … More high shear stress or modulators such as botrocetin, VWF binds to the platelet membrane GPIb-IX-V complex and initiates intracellular signals leading to platelet activation. In this study, we found that VacA induces increase of release of P selectin from platelet in a concentration-dependent manner. 120nM VacA induces maximum of release of P selection from platelets. VacA also induced increase of platelet aggregation stimulated by VWF binding to GPIb. It has been recently recognized that cell membranes are not uniform and that there are particular membrane regions rich in cholesterol and glycosphinglipids known as glycosphingolipid-enriched microdomains (GEMs, also known as raft). GEMs contain certain sets of signaling molecules whilst excluding others, and appear to provide platforms for signal transduction. Biotin-labelled VacA study revealed that VacA associates an unknown platelet receptor, which locates in GEMs. The analysis by CNBr-VacA showed that 130kDa of platelet glycoprotein is associated with VacA in platelet membranes. These results suggest that Helicobacter pylori cause platelet activation in VWF-GPIb-related pathways, leading to thrombus formation, and that mechanism of platelet activation induced by VacA would prevent thrombotic disorders. Less

特发性血小板减少性紫癜（ITP）是一种以自身抗体介导的血小板破坏为特征的疾病，可能是淋巴组织增生性自身免疫性疾病或感染性疾病的原发或继发疾病。越来越多的数据表明，幽门螺杆菌感染与特发性血小板减少性紫癜之间存在相关性，且根除幽门螺杆菌后血小板计数显著增加。这些结果表明，幽门螺杆菌感染诱导血小板活化血栓形成。本研究的目的是探讨幽门螺杆菌空泡毒素VacA诱导血小板活化的机制。血小板粘附于内皮下结构是止血和血栓形成的早期和关键事件。血管性血友病因子（vonWillebrand factor，VWF）是一种主要的粘附糖蛋白（GP），在高剪切应力条件下，如在小动脉和动脉毛细血管中发生的那些条件下，正常止血所需。存在下 ...更多信息 高剪切应力或调节剂如肉毒素、VWF与血小板膜GPIb-IX-V复合物结合并引发导致血小板活化的细胞内信号。在本研究中，我们发现VacA以浓度依赖的方式诱导血小板释放P选择素。120 nM VacA诱导血小板释放P选择素最大。VacA还可诱导VWF结合GPIb所刺激的血小板聚集增加。最近人们认识到，细胞膜是不均匀的，并且存在富含胆固醇和鞘糖脂的特定膜区域，称为鞘糖脂富集微结构域（GEM，也称为筏）。GEM包含某些信号分子集，同时排除其他信号分子，并且似乎为信号转导提供平台。生物素标记的VacA研究表明VacA与一种未知的血小板受体相关，该受体位于GEM中。CNBr-VacA分析表明，血小板膜上130 kDa的血小板糖蛋白与VacA结合。这些结果表明，幽门螺杆菌引起血小板活化的VWF-GPIb相关的途径，导致血栓形成，和VacA诱导的血小板活化的机制将防止血栓性疾病。少