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: Luigia Di Francesco, Licia Totani, Melania Dovizio, Antonio Piccoli, Andrea Di Francesco, Tania Salvatore, Assunta Pandolfi, Virgilio Evangelista, Ryan A Dercho, Francesca Seta, Paola Patrignani
• Journal: Circulation research (Circ Res) Vol. 104 Issue 4 Pg. 506-13 (Feb 27 2009) ISSN: 1524-4571 [Electronic] United States
• PMID: 19122175 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzofurans
• Cyclooxygenase Inhibitors
• Nitrobenzenes
• PTGIR protein, human
• Propionates
• RO3244794
• Receptors, Epoprostenol
• Receptors, Prostaglandin
• Sulfonamides
• Tumor Necrosis Factor-alpha
• N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
• 6-Ketoprostaglandin F1 alpha
• carboprostacyclin
• Dinoprost
• Epoprostenol
• HMOX1 protein, human
• Heme Oxygenase-1
• Cyclooxygenase 1
• Cyclooxygenase 2
• PTGS1 protein, human
• PTGS2 protein, human
• Dinoprostone
• Aspirin
• Prostaglandin D2

Topics

• 6-Ketoprostaglandin F1 alpha
• Aspirin (adverse effects, pharmacology)
• Atherosclerosis (chemically induced, enzymology)
• Benzofurans (pharmacology)
• Cells, Cultured
• Cyclooxygenase 1 (metabolism)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase Inhibitors (adverse effects, pharmacology)
• Dinoprost (metabolism)
• Dinoprostone (metabolism)
• Down-Regulation
• Endothelial Cells (drug effects, enzymology)
• Epoprostenol (analogs & derivatives, metabolism, pharmacology)
• Heme Oxygenase-1 (metabolism)
• Humans
• Inflammation (chemically induced, enzymology)
• Nitrobenzenes (adverse effects, pharmacology)
• Perfusion
• Propionates (pharmacology)
• Prostaglandin D2 (metabolism)
• Receptors, Epoprostenol
• Receptors, Prostaglandin (drug effects, metabolism)
• Stress, Mechanical
• Sulfonamides (adverse effects, pharmacology)
• Tumor Necrosis Factor-alpha (biosynthesis)
• Up-Regulation