Superoxide dismutase abolishes the platelet-derived growth factor-induced release of prostaglandin E2 by blocking induction of nitric oxide synthase: role of superoxide.
The ability of platelet-derived growth factor (PDGF) to induce prostaglandin E2 (PGE2) release in fibroblasts is abolished when copper-zinc superoxide dismutase activity is increased by transfection of an expression vector. The effect is specific to copper-zinc superoxide dismutase as glutathione peroxidase-overexpressing NIH3T3 cells, again produced by transfection of an expression vector, retain the ability to release PGE2 in response to growth factor stimulation. The defect in PDGF-induced PGE2 release occurs prior to action of prostaglandin H synthase/cyclooxygenase as release of arachadonic acid (in response to PDGF) does not occur in the superoxide dismutase-overexpressing clones. The defect in PDGF-induced release of PGE2 in superoxide dismutase-overexpressing clones differs from the defect found in pEJ-ras-transformed clones. The parent cells, the glutathione peroxidase-expressing cells, and the superoxide dismutase-overexpressing cells all release PGE2 in response to exogenous nitric oxide, whereas the pEJ-ras-transformed cells do not. The glutathione peroxidase-expressing cells also retained the ability to release nitrite in response to PDGF, whereas the superoxide dismutase-expressing clones do not. PDGF stimulates nitric oxide synthase activity in NIH3T3 cells, but not in the superoxide dismutase-expressing clones. These results indicate that superoxide dismutase overexpression blocks the PDGF-induced release of PGE2 by blocking induction of nitric oxide synthase. This indicates that the increase of nitric oxide synthase induced by PDGF is mediated in part by production of superoxide. These findings link cellular oxygen radical homeostasis to three different classes of messenger molecules (growth factors, nitric oxide, and prostaglandins).
Kelner
M J
MJ
Department of Pathology, University of California, San Diego 92103-8320, USA.
Uglik
S F
SF
D016475:3T3 Cells; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D002461:Cell Line, Transformed; D015232:Dinoprostone / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006706:Homeostasis; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000378:metabolism; D051379:Mice; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D009599:Nitroprusside / Q000494:pharmacology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
D010982:Platelet-Derived Growth Factor; D013481:Superoxides; D009599:Nitroprusside; D016718:Arachidonic Acid; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D013482:Superoxide Dismutase; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone