Abstract 19993: An Important Role for Akt3 in Platelet Activation and Thrombosis
Akt family of serine/threonine kinases includes three isoforms, Akt1, Akt2 and Akt3. Prior studies have reported that Akt1 and Akt2, but not Akt3, are expressed in platelets. Here we show that Akt3 is in fact the major Akt isoform expressed in platelets, and accounts for about 70% of total and phosphorylated Akt. Unlike Akt1 and Akt2 that are important in platelet secretion and aggregation induced by nearly all tested platelet agonists, Akt3−/− mice selectively exhibit impaired platelet aggregation and secretion induced only by low concentrations of thrombin receptor agonists and thromboxane A2 analog. The defect in the aggregation of Akt3−/− platelets is rescued by addition of a sub-threshold dose of ADP, indicating a primary role for Akt3 is in mediating platelet secretion. Akt3−/− platelets exhibit a significant reduction in thrombin-induced phosphorylation of glycogen synthase kinase 3β (GSK-3β) at Ser9, which is known to inhibit GSK-3β function. This result suggests that Akt3 is important in inhibiting GSK-3β in platelets. Treatment of wild type platelets with a GSK-3β selective inhibitor promoted thrombin induced platelet aggregation and secretion, but inhibited collagen induced aggregation and secretion. Accordingly, treatment of Akt3−/− platelets with a GSK-3β selective inhibitor rescued the defect of Akt3−/− platelets in thrombin-induced aggregation, suggesting that Akt3 promotes platelet activation by negatively regulating GSK-3β. Importantly, Akt3−/− mice showed significant retardation in FeCl3-induced carotid artery thrombosis in vivo. Thus, Akt3 plays an important role in platelet activation and in in vivo thrombosis, and the role of Akt3 in platelets appears to be distinct from that of Akt1 and Akt2.
- © 2010 by American Heart Association, Inc.