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.
Department of Applied Pharmacology, The National Heart and Lung Institute, Imperial College of Science and Technology, London, UK.
D
D
Bishop-Bailey
J R
JR
Pepper
S W
SW
Larkin
J A
JA
Mitchell
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