title: Autocrine function of inducible nitric oxide synthase and cyclooxygenase-2 in proliferation of human and rat pulmonary artery smooth-muscle cells: species variation.
abstract: Pulmonary hypertension is characterized by hypertrophy and hyperplasia of vascular smooth muscle occurring via an unknown mechanism. Cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) are expressed under inflammatory conditions and produce mediators that regulate growth in some tissues. We have therefore addressed the question of COX-2 and iNOS involvement in proliferation of human and rat pulmonary artery (PA) smooth-muscle cells (SMC). Interleukin (IL)-1beta suppressed proliferation of both human and rat PA SMC. Moreover, IL-1beta induced COX-2 expression in both cell types. By contrast, IL-1beta stimulated the expression of iNOS protein in rat cells only. COX-2 induced in human cells inhibited proliferation, whereas COX-2 products in rat cells were without affect. However, iNOS activity in rat cells suppressed their proliferation. We conclude that human and rat evolution has diverged such that COX-2 and iNOS, although induced by the same mediator, have different levels of activity and functions in the two species. In humans, induction of COX-2 during pulmonary hypertension may be beneficial for long-term treatment of this disease.
authors.affiliation: Unit of Critical Care, Imperial College School of Medicine at the National Heart and Lung Institute, Royal Brompton Hospital, London, United Kingdom.
authors.forename: K B
authors.initials: KB
authors.lastname: Jourdan
authors.forename: T W
authors.initials: TW
authors.lastname: Evans
authors.forename: N J
authors.initials: NJ
authors.lastname: Lamb
authors.forename: P
authors.initials: P
authors.lastname: Goldstraw
authors.forename: J A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D007189:Indans / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011651:Pulmonary Artery / Q000201:enzymology*; D051381:Rats
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D006146:Guanidines; D007189:Indans; D007375:Interleukin-1; D007527:Isoenzymes; C093700:L 745337; D008565:Membrane Proteins; D011464:Epoprostenol; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C043867:cicaprost; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin