Thromboxane A(2) receptor blockade suppresses intercellular adhesion molecule-1 expression by stimulated vascular endothelial cells

Inhibition of the thromboxane A(2)-synthesizing enzyme (DP-1904; [+/-]-6-[1-imidazolylmethyl]-5,6,7,8-tetrahydromaphthalene-2-carboxylic acid hydrochloride hemihydrate) reportedly suppresses intercellular adhesion molecule-1 (ICAM-1) expression on the surface of stimulated vascular endothelial cells (Ishizuka et al., 1994, Eur. J. Pharmacol. 262, 113). In the present study, thromboxane A(2) receptor antagonists suppressed the expression of ICAM-1 on the surface of human vascular endothelial cells that were stimulated by tumor necrosis factor alpha (TNF alpha), platelet activating factor (PAF), or U46619 (9,11-dideoxy-9 alpha,11 alpha-epoxymethanoprostaglandin F-2 alpha). Augmentation of ICAM-1 expression on human vascular endothelial cells stimulated by U46619 was suppressed by protein kinase C inhibitors. Thromboxane A(2) receptor antagonist suppressed U46619 stimulation of protein kinase C activity of a cell membrane fraction. These results indicate that in human vascular endothelial cells, thromboxane A(2), the production and secretion of which is stimulated by TNF alpha or PAF, binds to the thromboxane A(2) receptors on cell membranes and augments ICAM-1 expression on the cell surfaces mainly through protein kinase C.