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15-Oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase that Inhibits Endothelial Cell Proliferation

Commentary by Ian A. Blair

15-Oxo-eicosatetraenoic acid (15-oxo-ETE) was shown to arise from rabbit lung 15-hydroxyprostaglandin dehydrogenase-mediated oxidation of 15(S)-hydroxyeicosatetraenoic acid over thirty years ago by Dr. Richard Okita and his colleagues at the Medical College of Wisconsin (Bergholte et al. Arch Biochem Biophys. 1977;257:444). More recently, we identified 15-oxo-ETE as a metabolite of cyclooxygenase-2-mediated arachidonic acid metabolism (Lee et al. Chem Res Toxicol. 2007;20:665). However, this interesting arachidonic acid metabolite has remained a pharmacological curiosity for many years. Our new study has revealed a novel biological activity for 15-oxo-ETE, which has provided additional insight into 15-lipoxygenase-1-mediated signaling by monocyte/macrophages. When intracellular calcium concentrations are elevated, 15-lipoxygenase-1 is recruited to the inner side of the plasma membrane of monocytes/macrophages where it converts esterified arachidonic acid to 15(S)-hydroperoxyeicosatetraenoic acid.

Esterified 15(S)-hydroperoxyeicosatetraenoic acid is reduced to 15(S)-hydroxyeicosatetraenoic acid and released as the free acid by cytoplasmic phospholipase A2. The 15(S)-hydroxyeicosatetraenoic acid is then oxidized to 15-oxo-EET by 15-hydroxyprostaglandin dehydrogenase and conjugated to form a glutathione adduct, which is then hydrolyzed by ?-glutamyltranspeptidase to a cysteinylglycine-adduct. Released 15-oxo-ETE can inhibit endothelial cell proliferation, which could further prevent endothelial growth and that in turn could lead to the inhibition of angiogenesis. Dr. Ray DuBois when he was at Vanderbilt University demonstrated that the expression of 15-hydroxyprostaglandin dehydrogenase is down-regulated in colon cancer (Backlund et al. J Biol Chem. 2005:280:3217). In the absence of 15-hydroxyprostaglandin dehydrogenase no 15-oxo-ETE would be formed and therefore its anti-angiogenesis activity on endothelial cells would be lost. This could then in turn lead to increased tumor growth and metastasis. Therefore, these studies provide a pharmacological basis for the design of new targeted therapeutic strategies to inhibit angiogenesis, a pathway that is critical for both carcinogenesis and inflammation.

This then you can link to the actual “15-Oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase that Inhibits Endothelial Cell Proliferation” journal paper.

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