GSK3 beta is a negative regulator of platelet function and thrombosis

Glycogen synthase kinase (GSK)3 beta is a ser-thr kinase that is phosphorylated by the kinase Akt. Although Akt has been shown to regulate platelet function and arterial thrombosis, its effectors in platelets remain unknown. We show here that agonist-dependent phosphorylation of GSK3 beta in platelets is Akt dependent. To determine whether GSK3 beta regulates platelet function, platelets from mice lacking a single allele of GSK3 beta were compared with those of wild-type (WT) controls. GSK3 beta(+/-) platelets demonstrated enhanced agonist-dependent aggregation, dense granule secretion, and fibrinogen binding, compared with WT platelets. Treatment of human platelets with GSK3 inhibitors renders them more sensitive to agonist-induced aggregation, suggesting that GSK3 suppresses platelet function in vitro. Finally, the effect of GSK3 beta on platelet function in vivo was evaluated using 2 thrombosis models in mice. In the first, 80% of GSK3 beta(+/-) mice (n = 10) formed stable occlusive thrombi after ferric chloride carotid artery injury, whereas the majority Of wild-type mice (67%) formed no thrombi (n = 15). In a disseminated thrombosis model, deletion of a single allele of GSK3 beta in mice conferred enhanced sensitivity to thrombotic insult. Taken together, these results suggest that GSK3 beta acts as a negative regulator of platelet function in vitro and in vivo.