Platelet PI3Kβ and GSK3 regulate thrombus stability at a high shear rate
Platelet PI3Kβ and GSK3 regulate thrombus stability at a high shear rate
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DOI：
10.1182/blood-2014-07-588335
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发表时间：
2015-01-29
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：
Laurent, Pierre-Alexandre;Severin, Sonia;Gratacap, Marie-Pierre
IA类磷脂酰肌醇3-激酶β（PI 3 K β）被认为是动脉血栓形成的潜在药物靶点，动脉血栓形成是全球死亡的主要原因。在这里，我们表明，一个惊人的表型的小鼠与选择性p110 β缺失的巨核细胞系血栓不稳定性在高剪切速率，这是一个效果，没有检测到在血小板中的p110 α的情况下。在没有p110 β的情况下，在体外和体内均观察到高剪切率依赖性血栓不稳定性，并形成血小板栓塞。此外，当施加病理性高剪切时，需要PI 3 K β募集新的血小板至生长的血栓。用AZD 6482（一种选择性PI 3 K β抑制剂）处理人血液，在小鼠血小板中表现为p110 b缺失，这突出了p110 β激酶活性的作用。在生长的血小板血栓内，p110 β失活损害Akt的活化磷酸化和GSK 3的抑制磷酸化。与这些数据雅阁，GSK 3的药理学抑制恢复血栓稳定性。因此，血小板PI 3 K β在正常动脉剪切下对血栓生长和稳定性不是必需的，但在剪切速率升高时维持形成血栓的完整性方面具有特定和关键作用，表明PI 3 K β抑制剂治疗存在栓塞的潜在风险。
Class IA phosphoinositide 3-kinase beta (PI3K beta) is considered a potential drug target in arterial thrombosis, which is a major cause of death worldwide. Here we show that a striking phenotype of mice with selective p110 beta deletion in the megakaryocyte lineage is thrombus instability at a high shear rate, which is an effect that is not detected in the absence of p110 alpha in platelets. The high shear rate-dependent thrombus instability in the absence of p110 beta is observed both ex vivo and in vivo with the formation of platelet emboli. Moreover, PI3K beta is required for the recruitment of new platelets to a growing thrombus when a pathological high shear is applied. Treatment of human blood with AZD6482, a selective PI3K beta inhibitor, phenocopies p110b deletion in mouse platelets, which highlights the role of the kinase activity of p110 beta. Within the growing platelet thrombus, p110 beta inactivation impairs the activating phosphorylations of Akt and the inhibitory phosphorylation of GSK3. In accord with these data, pharmacologic inhibition of GSK3 restores thrombus stability. Thus, platelet PI3K beta is not essential for thrombus growth and stability at normal arterial shear but has a specific and critical role in maintaining the integrity of the formed thrombus on elevation of shear rate, suggesting a potential risk of embolization on treatment with PI3K beta inhibitors.