PI 3-kinase p110beta: a new target for antithrombotic therapy

Nat Med. 2005 May;11(5):507-14. doi: 10.1038/nm1232. Epub 2005 Apr 17.

Abstract

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 alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(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 PI3K p110beta as an important new target for antithrombotic therapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / pathology*
  • Bleeding Time
  • Blood Platelets / metabolism
  • Flow Cytometry
  • Isoenzymes / metabolism
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Platelet Adhesiveness / physiology*
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism*
  • Rheology
  • Serotonin / metabolism
  • Signal Transduction / physiology*
  • Thrombosis / metabolism*
  • Thrombosis / pathology
  • rap GTP-Binding Proteins / metabolism

Substances

  • Isoenzymes
  • Phosphoinositide-3 Kinase Inhibitors
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Serotonin
  • Rap1b protein, mouse
  • rap GTP-Binding Proteins