benzofurans and carboprostacyclin

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.

Topics: 6-Ketoprostaglandin F1 alpha; Aspirin; Atherosclerosis; Benzofurans; Cells, Cultured; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Down-Regulation; Endothelial Cells; Epoprostenol; Heme Oxygenase-1; Humans; Inflammation; Nitrobenzenes; Perfusion; Propionates; Prostaglandin D2; Receptors, Epoprostenol; Receptors, Prostaglandin; Stress, Mechanical; Sulfonamides; Tumor Necrosis Factor-alpha; Up-Regulation

Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Chemotaxis; Dinoprost; Dinoprostone; Endothelial Growth Factors; Endothelium, Vascular; Enzyme Inhibitors; Epoprostenol; Fatty Acids, Unsaturated; Fibroblast Growth Factor 2; Humans; Hydrazines; Lung Neoplasms; Lymphokines; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Neoplasm Metastasis; Neovascularization, Pathologic; Rats; Receptors, Thromboxane; Thromboxane A2; Thromboxane-A Synthase; Umbilical Veins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors