Thromboxane A2 receptor blockade suppresses intercellular adhesion molecule-1 expression by stimulated vascular endothelial cells.
Inhibition of the thromboxane A2-synthesizing enzyme (DP-1904: [+/-]-6-[1-imidazolylmethyl]-5,6,7,8-tetrahydronaphthalene-2-carbo xylic 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 A2 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 F2 alpha). Augmentation of ICAM-1 expression on human vascular endothelial cells stimulated by U46619 was suppressed by protein kinase C inhibitors. Thromboxane A2 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 A2, the production and secretion of which is stimulated by TNF alpha or PAF, binds to the thromboxane A2 receptors on cell membranes and augments ICAM-1 expression on the cell surfaces mainly through protein kinase C.
First Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
T
T
Ishizuka
K
K
Suzuki
M
M
Kawakami
T
T
Hidaka
Y
Y
Matsuki
H
H
Nakamura
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011869:Radioligand Assay; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D010972:Platelet Activating Factor; D011450:Prostaglandin Endoperoxides, Synthetic; D047428:Protein Kinase Inhibitors; D017482:Receptors, Thromboxane; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D000242:Cyclic AMP; D011494:Protein Kinases