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Mitsuhiro Uchiba, Kenji Okajima, Christoph Kaun, Johann Wojta, Bernd R. Binder
Inhibition of the endothelial cell activation by antithrombin in vitro
We examined whether antithrombin (AT) inhibits tumor necrosis factor (TNF)--induced endothelial cell activation to elucidate molecular mechanism(s) of the anti-inflammatory activity of AT. AT inhibited the increase in E-selectin expression in cultured human umbilical vein endothelial cells (HUVECs) stimulated with TNF-. In contrast, chemically modified AT that lacks affinity for heparin did not. AT inhibited the TNF--induced interaction of NF-B p65 with p300, a homologue of cAMP-responsive element binding protein (CREB)-binding protein (CBP). AT increased both intracellular levels of cAMP and binding of phosphorylated-CREB to DNA in HUVECs. Forskolin showed the inhibitory effect similar to that of AT and pretreatment of HUVECs with KT-5720, an inhibitor of protein kinase A, reversed the inhibitory effect of AT. These observations suggested that AT inhibited the TNF--induced increase in E-selectin expression in HUVECs by inhibiting the interaction of NF-B with CBP/p300 through cAMP-dependent protein kinase A-induced CREB activation. This inhibitory activity of AT might depend on its binding to heparin-like substances on the endothelial cell. Such an inhibitory effect of AT on TNF--induced endothelial cell activation might at least partly contribute to its anti-inflammatory activity.
Thrombosis and Haemostasis, Schattauer
Print ISSN: 0340-6245
Volume: 92, 12/2004
Pages: 1420 - 1427