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

Abstract

Abstract During platelet activation, phosphoinositide 3-kinases (PI3Ks) produce lipid second messengers participating in the regulation of functional responses. Here, we generated a megakaryocyte-restricted p110β null mouse model and demonstrated a critical role of PI3Kβ in platelet activation via an immunoreceptor tyrosine-based activation motif, the glyco-protein VI-Fc receptor γ-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 p110β 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 PI3Kβ is also acting downstream of αIIbβ3. 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 PI3Kβ is a potential target for antithrombotic drugs.