Identification of Structural-Activity Features of Long Chain Polyunsaturated Fatty Acid Epoxides in Angiogenesis

[Speaker] Rebekah Betts:1
[Co-author] Kin Sing Lee:1, Maris Cinelli:1, Joe Luca:1, Nick Confer:1
1:Pharmacology and Toxicology, Michigan State University, USA

The cytochrome P450-derived fatty acid epoxides are bioactive lipids with regulatory roles in a wide range of homeostatic and pathophysiological events. These lipid mediators are efficiently metabolized by mammalian soluble epoxide hydrolase enzyme (sEH) to corresponding 1,2-diols. Inhibition of sEH has been shown to be beneficial to human health via increasing concentrations of a variety of short-lived epoxylipids in vivo (2). Identifying the most potent polyunsaturated fatty acid (PUFA) epoxide species will provide insight on the effects of sEH inhibition. Recent studies have shown that the omega-6 epoxyeicosatrienoic acids (EETs) from arachidonic acid are pro-angiogenic, while the omega-3 docosahexaenoic acid (DHA)-derived epoxydocosapentaenoic acids (EDPs) inhibit angiogenesis, tumor growth, and metastasis (1). Given these findings, we explore the role of various long chain PUFA epoxides in angiogenesis. We tested a library of omega-3 and omega-6 epoxides in a newly developed high-throughput tube formation assay and found their effects are regiospecific and stereospecific; of note, the 19(S),20(R)-EDP stereoisomer inhibited endothelial cell tube formation less effectively than its respective racemic mixture. Here, we report the angiogenic activities of diverse omega-3 and omega-6 fatty acid epoxides that could be present in mammals from the diet, including the less explored epoxides from both omega-3 and omega-6 docosapentaenoic acid (DPA). We discuss the structure-activtity features of the most potent epoxide species and present methodology to synthesize and purify the regioisomers and stereoisomers of each series of epoxides. Ultimately, understanding activities of sEH substrates in specific regulatory environments will guide development of targeted sEH modulators that promote the beneficial effects of PUFA metabolites in human health and disease.

1. Zhang, G., et al. "Epoxy Metabolites of Docosahexaenoic Acid (DHA) Inhibit Angiogenesis, Tumor Growth, and Metastasis." Proceedings of the National Academy of Sciences, vol 110, no. 16, Mar. 2013, pp. 6530-6335.
2. Shen, Hong C., and Bruce D. Hammock. "Discovery of Inhibitors of Soluble Epoxide Hydrolase: A Target with Multiple Potential Therapeutic Indications." Journal of Medicinal Chemistry, vol. 55, no. 5, 2012, pp. 1789-1808.
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