Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Amy A. Rand, Bogdan Barnych, Christophe Morisseau, Tomas Cajka, Kin Sing Stephen Lee, Dipak Panigrahy, Bruce D. Hammock

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4370-4375
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number17
DOIs
StatePublished - Apr 25 2017

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Prostaglandin-Endoperoxide Synthases
Epoxide Hydrolases
Acids
Hydroxy Acids
Neoplasms
Growth
Cyclooxygenase 1
Cyclooxygenase 2
Arachidonic Acid
Oxygen Consumption
Cytochrome P-450 Enzyme System
Hydrolysis
Lipids

Keywords

  • Angiogenesis
  • Cyclooxygenase
  • Epoxyeicosatrienoic acids
  • Metabolism
  • Omega-6 fatty acids

ASJC Scopus subject areas

  • General

Cite this

Rand, A. A., Barnych, B., Morisseau, C., Cajka, T., Lee, K. S. S., Panigrahy, D., & Hammock, B. D. (2017). Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids. Proceedings of the National Academy of Sciences of the United States of America, 114(17), 4370-4375. https://doi.org/10.1073/pnas.1616893114

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids. / Rand, Amy A.; Barnych, Bogdan; Morisseau, Christophe; Cajka, Tomas; Lee, Kin Sing Stephen; Panigrahy, Dipak; Hammock, Bruce D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 17, 25.04.2017, p. 4370-4375.

Research output: Contribution to journalArticle

Rand, Amy A. ; Barnych, Bogdan ; Morisseau, Christophe ; Cajka, Tomas ; Lee, Kin Sing Stephen ; Panigrahy, Dipak ; Hammock, Bruce D. / Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 17. pp. 4370-4375.
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AU - Lee, Kin Sing Stephen

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AU - Hammock, Bruce D.

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N2 - 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.

AB - 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.

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