Induction of Prostacyclin by Steady Laminar Shear Stress Suppresses Tumor Necrosis Factor-α Biosynthesis via Heme Oxygenase-1 in Human Endothelial Cells

• Published in: Circulation research Vol. 104; no. 4; pp. 506 - 513
• Main Authors: Di Francesco, Luigia, Totani, Licia, Dovizio, Melania, Piccoli, Antonio, Di Francesco, Andrea, Salvatore, Tania, Pandolfi, Assunta, Evangelista, Virgilio, Dercho, Ryan A., Seta, Francesca, Patrignani, Paola
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 27.02.2009; Lippincott Williams & Wilkins
• Subjects: 6-Ketoprostaglandin F1 alpha; Aspirin - adverse effects; Aspirin - pharmacology; Atherosclerosis - chemically induced; Atherosclerosis - enzymology; Benzofurans - pharmacology; Biological and medical sciences; Cells, Cultured; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - adverse effects; Cyclooxygenase Inhibitors - pharmacology; Dinoprost - metabolism; Dinoprostone - metabolism; Down-Regulation; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Epoprostenol - analogs & derivatives; Epoprostenol - metabolism; Epoprostenol - pharmacology; Fundamental and applied biological sciences. Psychology; Heme Oxygenase-1 - metabolism; Humans; Inflammation - chemically induced; Inflammation - enzymology; Nitrobenzenes - adverse effects; Nitrobenzenes - pharmacology; Perfusion; Propionates - pharmacology; Prostaglandin D2 - metabolism; Receptors, Epoprostenol; Receptors, Prostaglandin - drug effects; Receptors, Prostaglandin - metabolism; Stress, Mechanical; Sulfonamides - adverse effects; Sulfonamides - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis; Up-Regulation; Vertebrates: cardiovascular system; Human; Prostaglandin-endoperoxide synthase; Endothelial cell; endothelial cells; Prostaglandin I2; Enzyme; Induction; Cytokine; cyclooxygenase; Biosynthesis; Vertebrata; Mammalia; prostanoids; tumor necrosis factor-α; Heme; Prostanoid; Shear stress; prostaglandins; Oxidoreductases; Circulatory system; Tumor necrosis factor α
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.108.191114

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)-α 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 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)F1α (the hydrolysis product of prostacyclin), PGE2, and PGD2. In contrast, TNF-α 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-α 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-α 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-α generation in human endothelial cells.