PI 3-kinase p110β : a new target for antithrombotic therapy.

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin α I I b β 3 (GPIIb-IIIa). In this study we have defined a key role for the Type la phosphoinositide 3-kinase (P13K) p110β isoform in regulating the formation and stability of integrin α I I b β 3 adhesion bonds, necessary for shear activation of platelets. Isoform-selective P13K p110β inhibitors have been developed which prevent formation of stable integrin α I I b β 3 adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define P13K p110β as an important new target for antithrombotic therapy.