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Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4370-4375. doi: 10.1073/pnas.1616893114. Epub 2017 Apr 10.

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids.

Author information

1
Department of Entomology and Nematology, University of California, Davis, CA 95616.
2
UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616.
3
West Coast Metabolomics Center, UC Davis Genome Center, University of California, Davis, CA 95616.
4
Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
5
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
6
Department of Entomology and Nematology, University of California, Davis, CA 95616; bdhammock@ucdavis.edu.

Abstract

Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.

KEYWORDS:

angiogenesis; cyclooxygenase; epoxyeicosatrienoic acids; metabolism; omega-6 fatty acids

PMID:
28396419
PMCID:
PMC5410821
DOI:
10.1073/pnas.1616893114
[Indexed for MEDLINE]
Free PMC Article

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