Resistance to thromboembolism in PI3Kgamma-deficient mice

FASEB J. 2001 Sep;15(11):2019-21. doi: 10.1096/fj.00-0810fje. Epub 2001 Jul 9.

Abstract

Platelet aggregation and subsequent thrombosis are the major cause of ischemic diseases such as heart attack and stroke. ADP, acting via G protein-coupled receptors (GPCRs), is an important signal in thrombus formation and involves activation of phosphoinositide 3-kinases (PI3K). When platelets from mice lacking the G protein-activated PI3Kgamma isoform were stimulated with ADP, aggregation was impaired. Collagen or thrombin, however, evoked a normal response. ADP stimulation of PI3Kgamma-deficient platelets resulted in decreased PKB/Akt phosphorylation and alpha(IIb)beta(3) fibrinogen receptor activation. These effects did not influence bleeding time but protected PI3Kgamma-null mice from death caused by ADP-induced platelet-dependent thromboembolic vascular occlusion. This result demonstrates an unsuspected, well-defined role for PI3Kgamma downstream of ADP and suggests that pharmacological targeting of PI3Kgamma has a potential use as antithrombotic therapy.

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Adenosine Diphosphate / pharmacology
  • Animals
  • Bleeding Time
  • Blood Platelets / metabolism
  • Class Ib Phosphatidylinositol 3-Kinase
  • Fibrinogen / metabolism
  • GTP-Binding Proteins / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / physiology*
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / physiology*
  • Phosphorylation
  • Platelet Aggregation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptors, Cell Surface / metabolism
  • Thromboembolism / metabolism*

Substances

  • Isoenzymes
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • Adenosine Diphosphate
  • Fibrinogen
  • Phosphatidylinositol 3-Kinases
  • Class Ib Phosphatidylinositol 3-Kinase
  • Pik3cg protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • GTP-Binding Proteins