Abstract 15801: Src Activation is an Essential Step in the Hypercoagulability Induced by the Integrin β3 Pro33 Polymorphism in the Mouse
The plasma-membrane integrin αIIbβ3 (CD41/CD61, GPIIbIIIa) plays a critical role in the activation of circulating platelets during clot formation. The integrin β3 PlA1 and PlA2 polymorphisms correspond to Leu33 and Pro33 coding variants, respectively, where the Pro33 allele is associated with increased risk for coronary thrombosis and stroke. While the association of the Pro33 coding variant with enhanced platelet aggregation has been established in humans, the mechanism by which this amino-acid substitution modifies αIIbβ3 adhesion and signaling remains unknown. In this study we introduced, through homologous recombination, the Pro32Pro33mutation in the mouse integrin β3. Platelets isolated from Pro32Pro33 homozygous mice (KI) showed increased adhesion and spreading onto fibrinogen, indicating that this substitution is sufficient to enhance integrin αIIbβ3 function. Consistent with alterations in human platelets, bleeding and clotting times are significantly decreased in Pro32Pro33 mice, whereas venous thromboembolism was increased when compared to wild-type controls. These effects are paralleled by differential agonist-dependent responses to PAR-4 agonist, at least in part due to enhanced Src activation in Pro32Pro33 platelets. Clotting times are rescued to wild-type levels by acute in vivo treatment with the Src inhibitor SKI-606. These data illustrate that the Pro32Pro33 changes in extracellular PSI domains in integrin β3 are sufficient influence cell signaling and thus alter platelet function in vivo.
- © 2013 by American Heart Association, Inc.