Glycogen Synthase Kinase-3 Mediates Endothelial Cell Activation by Tumor Necrosis Factor-α

Background— Endothelial cell transformation to a thrombogenic and inflammatory phenotype plays an important role in the pathogenesis of atherothrombosis, but the responsible signaling pathways remain to be elucidated. This study was designed to investigate the regulatory role of glycogen synthase kinase-3 (GSK-3) in tissue factor (TF) and vascular cell adhesion molecule (VCAM)-1 expression in tumor necrosis factor (TNF)-α–stimulated endothelial cells. Methods and Results— In human endothelial cells, TNF-α as well as thrombin induced rapid and transient dephosphorylation and hence, activation of GSK-3. A GSK-3 inhibitor, LiCl, suppressed TNF-α– and thrombin-induced TF and VCAM-1 expression, whereas NaCl had no effect. A specific GSK-3 inhibitor, TDZD-8, mimicked the inhibitory effects of lithium. GSK-3 inhibition also significantly suppressed the TNF-α–induced increase in TF activity and VCAM-1 cell-surface expression. The luciferase reporter system demonstrated that regulation of TF and VCAM-1 expression ...