title: Induction of prostacyclin by steady laminar shear stress suppresses tumor necrosis factor-alpha biosynthesis via heme oxygenase-1 in human endothelial cells.
abstract: Cyclooxygenase (COX)-2 is among the endothelial genes upregulated by uniform laminar shear stress (LSS), characteristically associated with atherosclerotic lesion-protected areas. We have addressed whether the induction of COX-2-dependent prostanoids in endothelial cells by LSS plays a role in restraining endothelial tumor necrosis factor (TNF)-alpha generation, a proatherogenic cytokine, through the induction of heme oxygenase-1 (HO)-1, an antioxidant enzyme. In human umbilical vein endothelial cells (HUVECs) exposed to steady LSS of 10 dyn/cm(2) for 6 hours, COX-2 protein was significantly induced, whereas COX-1 and the downstream synthases were not significantly modulated. This was associated with significant (P<0.05) increase of 6-keto-prostaglandin (PG)F(1alpha) (the hydrolysis product of prostacyclin), PGE(2), and PGD(2). In contrast, TNF-alpha released in the medium in 6 hours (3633+/-882 pg) or detected in cells lysates (1091+/-270 pg) was significantly (P<0.05) reduced versus static condition (9100+/-2158 and 2208+/-300 pg, respectively). Coincident induction of HO-1 was detected. The finding that LSS-dependent reduction of TNF-alpha generation and HO-1 induction were abrogated by the selective inhibitor of COX-2 NS-398, the nonselective COX inhibitor aspirin, or the specific prostacyclin receptor (IP) antagonist RO3244794 illuminates the central role played by LSS-induced COX-2-dependent prostacyclin in restraining endothelial inflammation. Carbacyclin, an agonist of IP, induced HO-1. Similarly to inhibition of prostacyclin biosynthesis or activity, the novel imidazole-based HO-1 inhibitor QC15 reversed TNF-alpha reduction by LSS. These findings suggest that inhibition of COX-2-dependent prostacyclin might contribute to acceleration of atherogenesis in patients taking traditional nonsteroidal antiinflammatory drugs (NSAIDs) and NSAIDs selective for COX-2 through downregulation of HO-1, which halts TNF-alpha generation in human endothelial cells.
authors.affiliation: Department of Medicine and Aging, G d'Annunzio University, Chieti, Italy.
authors.forename: Luigia
authors.initials: L
authors.lastname: Di Francesco
authors.forename: Licia
authors.initials: L
authors.lastname: Totani
authors.forename: Melania
authors.initials: M
authors.lastname: Dovizio
authors.forename: Antonio
authors.initials: A
authors.lastname: Piccoli
authors.forename: Andrea
authors.initials: A
authors.lastname: Di Francesco
authors.forename: Tania
authors.initials: T
authors.lastname: Salvatore
authors.forename: Assunta
authors.initials: A
authors.lastname: Pandolfi
authors.forename: Virgilio
authors.initials: V
authors.lastname: Evangelista
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Dercho
authors.forename: Francesca
authors.initials: F
authors.lastname: Seta
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology*; D001572:Benzofurans / Q000494:pharmacology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology*; D009578:Nitrobenzenes / Q000009:adverse effects / Q000494:pharmacology; D010477:Perfusion; D011422:Propionates / Q000494:pharmacology; D015230:Prostaglandin D2 / Q000378:metabolism; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000187:drug effects / Q000378:metabolism; D013314:Stress, Mechanical; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation
chemical_list: D001572:Benzofurans; D016861:Cyclooxygenase Inhibitors; D009578:Nitrobenzenes; C113936:PTGIR protein, human; D011422:Propionates; C515593:RO3244794; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015121:6-Ketoprostaglandin F1 alpha; C026678:carboprostacyclin; D015237:Dinoprost; D011464:Epoprostenol; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D015232:Dinoprostone; D001241:Aspirin; D015230:Prostaglandin D2