Deletion of the p110β isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo
Deletion of the p110β isoform of phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and thrombus formation in vitro and in vivo
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DOI：
10.1182/blood-2009-04-217224
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发表时间：
2010-03-11
期刊：
影响因子：
20.3
通讯作者：
Gratacap, Marie-Pierre
中科院分区：
文献类型：
--
作者：
Martin, Valerie;Guillermet-Guibert, Julie;Gratacap, Marie-Pierre
在血小板活化过程中，磷脂酰肌醇3-激酶(PI3Ks)产生脂质第二信使，参与功能反应的调节。在这里，我们建立了一个巨核细胞限制性p110β缺失的小鼠模型，并展示了PI3Kβ通过基于免疫受体酪氨酸的激活基序-糖蛋白VI-Fc受体伽马链复合体-在血小板激活中的关键作用，以及它在G蛋白偶联受体反应中的作用。有趣的是，经免疫受体酪氨酸激活基序或G蛋白偶联受体刺激的p110γ-零血小板中，磷脂酰肌醇3，4，5-三磷酸的产生和蛋白激酶B/Akt的激活被强烈地抑制。功能研究表明，在血流状态下，纤维蛋白凝块回缩明显延迟，这些血小板几乎完全不能附着在纤维蛋白原上，这表明PI3Kβ也在IIbβ3的下游发挥作用。体内研究表明，这些小鼠有正常的出血时间，对急性肺血栓栓塞症没有保护作用，但对颈动脉FeCl3损伤后的血栓具有抵抗力，表明PI3Kβ是抗血栓药物的潜在靶点。(血。2010；115：2008-2013)
During platelet activation, phosphoinositide 3-kinases (PI3Ks) produce lipid second messengers participating in the regulation of functional responses. Here, we generated a megakaryocyte-restricted p110 beta null mouse model and demonstrated a critical role of PI3K beta in platelet activation via an immunoreceptor tyrosine-based activation motif, the glycoprotein VI-Fc receptor gamma-chain complex, and its contribution in response to G-protein-coupled receptors. Interestingly, the production of phosphatidylinositol 3,4,5-trisphosphate and the activation of protein kinase B/Akt were strongly inhibited in p110 gamma null platelets stimulated either via immunoreceptor tyrosine-based activation motif or G-protein-coupled receptors. Functional studies showed an important delay in fibrin clot retraction and an almost complete inability of these platelets to adhere onto fibrinogen under flow condition, suggesting that PI3K beta is also acting downstream of IIb beta 3. In vivo studies showed that these mice have a normal bleeding time and are not protected from acute pulmonary thromboembolism but are resistant to thrombosis after FeCl3 injury of the carotid, suggesting that PI3K beta is a potential target for antithrombotic drugs. (Blood. 2010; 115: 2008-2013)