Differential induction of cyclooxygenase-2 in human arterial and venous smooth muscle: role of endogenous prostanoids.
Two isoforms of cyclooxygenase (COX) have been identified: a constitutive isoform (COX-1), found in abundance in platelets and the vascular endothelium, and an "inflammatory" cytokine-inducible isoform (COX-2). Because COX metabolites regulate vascular smooth muscle cell (SMC) function and the interaction between the vessel and circulating components, we have investigated the possibility that COX-2 can be induced in human arterial or venous SMC. Untreated venous or arterial cells contained undetectable levels of COX-1 or COX-2 and released low levels of metabolites. After stimulation with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and bacterial lipopolysaccharide, both venous and arterial SMC expressed COX-2 protein and released increased amounts of prostaglandins. In addition, the induced release of PGE2 was inhibited by the COX-2-selective inhibitor, L-745,337. When cells were treated with the mixture of cytokines, venous SMC expressed greater amounts of COX-2 protein and released more prostaglandins than arterial SMC. Furthermore, when COX-2 activity was blocked by L-745,337, COX-2 expression in arterial SMC, but not in venous SMC, increased. Thus, this article describes, for the first time, that COX-2 is expressed in greater amounts in venous SMC than in arterial SMC. Moreover, we show that this "differential induction" is due to a negative-feedback pathway for COX-2 expression in arterial SMC but not in venous SMC. The ability of COX-2 activity to limit COX-2 expression in some cells but not others may contribute to the highly developed mechanisms involved in prostanoid release.
Bishop-Bailey
D
D
Department of Applied Pharmacology, The National Heart and Lung Institute, Imperial College of Science and Technology, London, UK.
Pepper
J R
JR
Larkin
S W
SW
Mitchell
J A
JA
D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008323:Mammary Arteries / Q000166:cytology; D008565:Membrane Proteins; D008934:Mitogens / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000502:physiology*; D012501:Saphenous Vein / Q000166:cytology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007189:Indans; D007375:Interleukin-1; D007527:Isoenzymes; C093700:L 745337; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D008934:Mitogens; D011453:Prostaglandins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; D007213:Indomethacin