Glycogen synthase kinase-3 mediates endothelial cell activation by tumor necrosis factor-alpha

Article

关键词: CORONARY ATHEROSCLEROTIC PLAQUES;    TISSUE FACTOR EXPRESSION;    I-KAPPA-B;    ADHESION MOLECULE-1;    PROTEIN-KINASE;    BETA-CATENIN;    THROMBIN STIMULATION;    ALZHEIMERS-DISEASE;    SKELETAL-MUSCLE;    GENE-EXPRESSION;   

DOI  :  10.1161/CIRCULATIONAHA.105.564112

来源: SCIE

【 摘 要 】

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)- alpha - stimulated endothelial cells. Methods and Results - In human endothelial cells, TNF- alpha as well as thrombin induced rapid and transient dephosphorylation and hence, activation of GSK- 3. A GSK- 3 inhibitor, LiCl, suppressed TNF- alpha - 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- alpha - induced increase in TF activity and VCAM- 1 cell- surface expression. The luciferase reporter system demonstrated that regulation of TF and VCAM- 1 expression by GSK- 3 was mediated at the transcriptional level. The TNF- alpha - induced increase in nuclear factor ( NF)- kappa B DNA- binding activity was significantly suppressed by TDZD- 8. TDZD- 8 completely prevented the TNF- alpha - induced inhibitor of NF- kappa B ( I kappa B)- alpha degradation but had no effect on I kappa B- kinase- beta phosphorylation. Conclusions - GSK- 3 regulates TNF- alpha - induced I kappa B- alpha degradation and NF- kappa B activation independent of I kappa B- kinase- beta and subsequent induction of TF and VCAM- 1 expression in human endothelial cells. This study provides the experimental basis for a novel strategy of using GSK- 3 inhibition to treat atherothrombotic vascular disease.

【 授权许可】

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