| First Author | Laurent PA | Year | 2015 |
| Journal | Blood | Volume | 125 |
| Issue | 5 | Pages | 881-8 |
| PubMed ID | 25398937 | Mgi Jnum | J:221208 |
| Mgi Id | MGI:5638494 | Doi | 10.1182/blood-2014-07-588335 |
| Citation | Laurent PA, et al. (2015) Platelet PI3Kbeta and GSK3 regulate thrombus stability at a high shear rate. Blood 125(5):881-8 |
| abstractText | Class IA phosphoinositide 3-kinase beta (PI3Kbeta) 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 p110beta 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 p110alpha in platelets. The high shear rate-dependent thrombus instability in the absence of p110beta is observed both ex vivo and in vivo with the formation of platelet emboli. Moreover, PI3Kbeta 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 PI3Kbeta inhibitor, phenocopies p110beta deletion in mouse platelets, which highlights the role of the kinase activity of p110beta. Within the growing platelet thrombus, p110beta 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 PI3Kbeta 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 PI3Kbeta inhibitors. |
