title: Endothelin-1 induces cyclooxygenase-2 expression and generation of reactive oxygen species in endothelial cells.
abstract: Since both endothelin-1 (ET-1) and aldosterone have been shown to induce expression of several pro-inflammatory genes, including cyclooxygenase-2 (COX-2), in the vasculature as a cardiovascular risk hormone, the present study was undertaken to examine the effects of ET-1 and aldosterone on COX-2 gene expression as measured by a real-time reverse transcriptase-polymerase chain reaction in aortic endothelial cells. Treatment with ET-1(10 M) markedly upregulated COX-2 mRNA levels in rat endothelial cells, whereas aldosterone (10 M) did not show any effect. The ET-1-induced COX-2 upregulation was inhibited by pretreatment with a non-selective endothelin receptor antagonist (TAK044), a protein kinase C inhibitor (GF109203X), and a MEK inhibitor (PD98059). Furthermore, ET-1 increased intracellular reactive oxygen species generation as estimated by the measurement of dichlorofluorescein fluorescence, whose effect was blocked by a COX-2 inhibitor (NS398). Our data show that ET-1 induces COX-2 upregulation in rat endothelial cells via a protein kinase C-dependent and extracellular signal-regulated kinase-dependent pathway, which may largely contribute to the generation of intracellular reactive oxygen species.
authors.affiliation: Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Sugiyama
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Ryuji
authors.initials: R
authors.lastname: Sato
authors.forename: Nozomi
authors.initials: N
authors.lastname: Fukai
authors.forename: Naoko
authors.initials: N
authors.lastname: Ozawa
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D000450:Aldosterone / Q000378:metabolism; D000818:Animals; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004790:Enzyme Induction; D005419:Flavonoids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017466:Receptors, Endothelin / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D009578:Nitrobenzenes; D010456:Peptides, Cyclic; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D017466:Receptors, Endothelin; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C088196:TAK 044; D000450:Aldosterone; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D011493:Protein Kinase C; D020929:Mitogen-Activated Protein Kinase Kinases; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one