title: Cyclooxygenase-2 acts as an endogenous brake on endothelin-1 release by human pulmonary artery smooth muscle cells: implications for pulmonary hypertension.
abstract: Endothelin-1 is a potent vasoconstrictor and comitogen for vascular smooth muscle. As such, it has been implicated in pulmonary vascular remodeling and in the development of pulmonary hypertension. Prostacyclin has been shown to be an effective therapy for human pulmonary hypertension, reducing morbidity and mortality, although the mechanism of its action is unknown. Here, we show that the combination of TNF-alpha and IFN-gamma induces the release of endothelin-1 from human pulmonary artery smooth muscle cells via increased transcription of prepro endothelin-1. The release of endothelin-1 and the transcription of prepro endothelin-1 mRNA were inhibited by the activity of coinduced cyclooxygenase-2. Endothelin-1 release was also inhibited by a prostacyclin-mimetic (cicaprost). Thus, under inflammatory conditions, in which vascular smooth muscle is an important source of endothelin-1, the induction of cyclooxygenase-2 represents an endogenous "braking" mechanism. In addition, the beneficial effects of prostacyclin in the treatment of pulmonary hypertension may be caused, at least in part, by the inhibition of endothelin-1 release. Finally, we suggest that these observations may help to explain why patients with pulmonary hypertension experience exacerbations after taking indomethacin and that the newly introduced selective cyclooxygenase-2 inhibitors may increase endothelin-1 production in susceptible patients, leading to vascular remodeling and the development of pulmonary hypertension.
authors.affiliation: Unit of Critical Care Medicine, Imperial College School of Medicine, Royal Brompton Hospital, London, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Wort
authors.forename: Mandy
authors.initials: M
authors.lastname: Woods
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Evans
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000242:Cyclic AMP / Q000378:metabolism; D051546:Cyclooxygenase 2; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008565:Membrane Proteins; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D019332:Endothelin-1; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D011464:Epoprostenol; D000242:Cyclic AMP; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C043867:cicaprost