15-oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase That Inhibits Endothelial Cell Proliferation

• DOI: 10.1124/mol.109.057489
• Publication Date: 2009-06-18T00:51:03Z
• Authors: Cong Wei; Peijuan Zhu; Sumit J. Shah; Ian A. Blair
• Keywords: 0301 basic medicine; 0303 health sciences; Macrophages; Endothelial Cells; Arachidonic Acids; Monocytes; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Hydroxyprostaglandin Dehydrogenases; Animals; Humans; Cell Proliferation

The formation of 15-oxo-5,8,11,13-(<i>Z</i>,<i>Z</i>,<i>Z</i>,<i>E</i>)-eicosatetraenoic acid (15-oxo-ETE) as a product from rabbit lung 15-hydroxyprostaglandin dehydrogenase (PGDH)-mediated oxidation 15(<i>S</i>)-hydroperoxy-5,8,11,13-(<i>Z</i>,<i>Z</i>,<i>Z</i>,<i>E</i>)-eicosatetraenoic was first reported more than 30 years ago. However, the pharmacological significance 15-oxo-ETE has never been established. We have now evaluated 15-lipoxygenase (LO)-1-mediated arachidonic (AA) metabolism to in human monocytes and mouse RAW macrophages that stably express 15-LO-1 (R15L cells). A targeted lipidomics approach used identify quantify oxidized lipids were formed. found be major AA-derived LO metabolite when AA given exogenously or released endogenous esterified lipid stores by calcium ionophore (CI) calcimycin (A-23187). This established R15L cells useful vitro model system. Pretreatment with cinnamyl-3,4-dihydroxycyanocinnamate significantly inhibited AA- CI-mediated production [15(<i>S</i>)-HETE] 15-oxo-ETE, confirming role mediating formation. Furthermore, 15(<i>S</i>)-HETE metabolized primarily 15-oxo-ETE. (PGDH) inhibitor 5-[[4-(ethoxycarbonyl)phenyl]azo]-2-hydroxy-benzeneacetic (CAY10397) reduced 15(<i>S</i>)-HETE-mediated dose-dependent manner. confirmed macrophage-derived 15-PGDH responsible for catalyzing conversion Finally, shown inhibit proliferation vascular vein endothelial suppressing DNA synthesis, implicating potential antiangiogenic role. is report describing biosynthesis macrophage/monocytes its ability cell proliferation.