| First Author | Laurent PA | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 9 | Pages | 2041-2053 |
| PubMed ID | 30354258 | Mgi Jnum | J:285110 |
| Mgi Id | MGI:6385412 | Doi | 10.1161/ATVBAHA.118.311410 |
| Citation | Laurent PA, et al. (2018) Impact of PI3Kalpha (Phosphoinositide 3-Kinase Alpha) Inhibition on Hemostasis and Thrombosis. Arterioscler Thromb Vasc Biol 38(9):2041-2053 |
| abstractText | Objective- PI3Kalpha (phosphoinositide 3-kinase alpha) is a therapeutic target in oncology, but its role in platelets and thrombosis remains ill characterized. In this study, we have analyzed the role of PI3Kalpha in vitro, ex vivo, and in vivo in 2 models of arterial thrombosis. Approach and Results- Using mice selectively deficient in p110alpha in the megakaryocyte lineage and isoform-selective inhibitors, we confirm that PI3Kalpha is not mandatory but participates to thrombus growth over a collagen matrix at arterial shear rate. Our data uncover a role for PI3Kalpha in low-level activation of the GP (glycoprotein) VI-collagen receptor by contributing to ADP secretion and in turn full activation of PI3Kbeta and Akt/PKB (protein kinase B). This effect was no longer observed at high level of GP VI agonist concentration. Our study also reveals that over a vWF (von Willebrand factor) matrix, PI3Kalpha regulates platelet stationary adhesion contacts under arterial flow through its involvement in the outside-in signaling of vWF-engaged alphaIIbbeta3 integrin. In vivo, absence or inhibition of PI3Kalpha resulted in a modest but significant decrease in thrombus size after superficial injuries of mouse mesenteric arteries and an increased time to arterial occlusion after carotid lesion, without modification in the tail bleeding time. Considering the more discrete and nonredundant role of PI3Kalpha compared with PI3Kbeta, selective PI3Kalpha inhibitors are unlikely to increase the bleeding risk at least in the absence of combination with antiplatelet drugs or thrombopenia. Conclusions- This study provides mechanistic insight into the role of PI3Kalpha in platelet activation and arterial thrombosis. |
