Abstract
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 metabolized efficiently by the 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 metabolites 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 are interested in exploring the roles 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 was a less effective inhibitor of endothelial cell tube formation 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 will discuss the structure‐activity features of the most potent epoxide species and also 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.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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