PI 3-kinase p110β:: a new target for antithrombotic therapy
PI 3-kinase p110β:: a new target for antithrombotic therapy
复制标题
DOI：
10.1038/nm1232
复制
发表时间：
2005-05-01
期刊：
影响因子：
82.9
通讯作者：
Salem, HH
中科院分区：
文献类型：
--
作者：
Jackson, SP;Schoenwaelder, SM;Salem, HH
血管损伤部位的血小板活化对于止血至关重要;然而，动脉粥样硬化斑块破裂区域的血小板过度积聚可导致动脉血栓的形成，从而诱发急性心肌梗死和缺血性卒中等疾病。流变学紊乱（高剪切应力）通过增强血小板整合素α（IIb）β（3）（GPIIb-IIIa）的粘附和信号传导功能在促进动脉血栓形成中具有重要作用。在这项研究中，我们已经确定了Ia型磷酸肌醇3-激酶（PI 3 K）p110 β亚型在调节血小板剪切活化所必需的整合素α（IIb）β（3）粘附键的形成和稳定性中的关键作用。已经开发了异构体选择性PI 3 K p110 β抑制剂，其防止形成稳定的整合素α（IIb）β（3）粘附接触，导致缺陷性血小板血栓形成。在体内，这些抑制剂消除闭塞性血栓形成，但不延长出血时间。这些研究将PI 3 K p110 β定义为抗血栓治疗的重要新靶点。
Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances ( high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110 beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110 beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110 beta as an important new target for antithrombotic therapy.