Synthesis of cyclooxygenase metabolites of 8,9-epoxyeicosatrienoic acid (EET): 11- and 15-hydroxy 8,9-EETs

Barnych, Bogdan; Rand, Amy A.; Čajka, Tomáš; Lee, Kin Sing Stephen

doi:10.1039/c7ob00789b

Cited by 6 publications

(8 citation statements)

References 36 publications

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“…We and others have shown that two regioisomers form from the metabolism of 8,9-EET by COX, 8,9,11-EHET and 8,9,15-EHET (38,39,44), but the formation of these metabolites has not been demonstrated in endothelial cells. To investigate this, we dosed HAECs with 8,9-EET (1 µM) with and without t-TUCB and PDBu and incubated the cells for 20 h. The media and cell lysates were collected, extracted, and analyzed for 8,9-EET and its sEH and COX products using LC/MS/MS.…”

Section: Cox-2 Metabolizes 89-eet To Form 8911-ehet and 8915-ehet In Haecsmentioning

confidence: 82%

“…We have previously demonstrated that 8,9-EET converts to 8,9,11-EHET using purified ovine COX-1 and human recombinant COX-2 enzymes (38,39). It was therefore surprising that 8,9-EET produced 8,9-DHET as its sole metabolite, irrespective of the presence of COX-1.…”

Section: Discussionmentioning

confidence: 99%

“…The 5,6-EET forms prostaglandin (5,6-epoxy-PGE 1 and hydroxyl-PGI 1 ) (38,(40)(41)(42), thromboxane (5-hydroxy-6,9-epoxy-thromboxane B 1 ), and hydroxylated (5,6-epoxy-12-hydroxyheptadecadienoic acid) products (43). 8,9-EET and 11,12-EET are both capable of being metabolized by COX-1 and COX-2 but form only hydroxylated products (38,39). The hydroxylation of 8,9-EET has also been demonstrated in human platelets and ram seminal vesicles (44).…”

mentioning

confidence: 99%

“…This has been partly due to the assumption that the presence of an epoxide on the 8,9-, 11,12-, and 14,15-positions of ARA would prevent the usual endoperoxide formation and limit reactivity. We were the first to examine the reactivity of the four EET regioisomers with purified COX-1 and COX-2 (38,39). The 5,6-EET forms prostaglandin (5,6-epoxy-PGE 1 and hydroxyl-PGI 1 ) (38,(40)(41)(42), thromboxane (5-hydroxy-6,9-epoxy-thromboxane B 1 ), and hydroxylated (5,6-epoxy-12-hydroxyheptadecadienoic acid) products (43).…”

mentioning

confidence: 99%

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Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2

Rand

Rajamani

Kodani

et al. 2019

Journal of Lipid Research

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Supplementary key words arachidonic acid • endothelial cells • cyclooxygenase 2 • mass spectrometry • cancer • metabolism • soluble epoxide hydrolase • angiogenesis Epoxyeicosatrienoic acids (EETs) are biologically active omega-6 fatty acids generated through the cytochrome P450 (CYP) oxidation of arachidonic acid (ARA). Endothelial cells express endogenous levels of CYP2B, CYP2C, and CYP2J subfamilies, which form four EET regioisomers (5,8,11,and 14, (1, 2). EETs can also be formed by other CYPs, particularly when they are induced (3). The EETs act in part to change the membrane potential and tone of the vascular wall; they are strong vasodilators that lead to reduced blood pressure (4, 5) and are endothelium-derived hyperpolarizing factors that activate Ca 2+ -activated K + channels in vascular smooth muscle cells and coronary arteries (6, 7). EETs also act as secondary messengers in numerous signal-transduction pathways involved in inflammation (8), pain (9), bone growth (10), cell migration (11), apoptosis (12), platelet aggregation (13), and hypoxia/reoxygenation injury (14). Multiple studies have also demonstrated that EETs stimulate endothelial cell proliferation and angiogenesis (1,(15)(16)(17)(18)(19)(20)(21)(22)(23).Angiogenesis is a tightly regulated physiological process that provides oxygen during tissue repair and growth but is also central to the growth and spread of tumors. EETs, Abstract Epoxyeicosatrienoic acids (EETs) are formed from the metabolism of arachidonic acid by cytochrome P450s. EETs promote angiogenesis linked to tumor growth in various cancer models that is attenuated in vivo by cyclooxygenase 2 (COX-2) inhibitors. This study further defines a role for COX-2 in mediating endothelial EET metabolism promoting angiogenesis. Using human aortic endothelial cells (HAECs), we quantified 8,9-EET-induced tube formation and cell migration as indicators of angiogenic potential in the presence and absence of a COX-2 inducer [phorbol 12,13-dibutyrate (PDBu)]. The angiogenic response to 8,9-EET in the presence of PDBu was 3-fold that elicited by 8,9-EET stabilized with a soluble epoxide hydrolase inhibitor (t-TUCB). Contributing to this response was the COX-2 metabolite of 8,9-EET, the 11-hydroxy-8,9-EET (8,9,11-EHET), which exogenously enhanced angiogenic responses in HAECs at levels comparable to those elicited by vascular endothelial growth factor (VEGF). In contrast, the 15-hydroxy-8,9-EET isomer was also formed but inactive. The 8,9,11-EHET also promoted expression of the VEGF family of tyrosine kinase receptors. These results indicate that 8,9-EET-stimulated angiogenesis is enhanced by COX-2 metabolism in the endothelium through the formation of 8,9,11-EHET. This alternative pathway for the metabolism of 8,9-EET may be particularly important in regulating angiogenesis under circumstances in which COX-2 is induced, such as in cancer tumor growth and inflammation.-Rand, A. A

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Section: Cox-2 Metabolizes 89-eet To Form 8911-ehet and 8915-ehet In Haecsmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2

Rand

Rajamani

Kodani

et al. 2019

Journal of Lipid Research

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“…2001 ) and interfere with neutrophil mediated clearance of pathogens ( Thompson and Hammock 2007 ). In addition, 8(9)-EET is also a ligand of

and has broad ranging functions including anti-inflammatory and anti-hypertensive effects ( Barnych et al. 2017 ; Bystrom et al.…”

Section: Discussionmentioning

confidence: 99%

Cross-Sectional Estimation of Endogenous Biomarker Associations with Prenatal Phenols, Phthalates, Metals, and Polycyclic Aromatic Hydrocarbons in Single-Pollutant and Mixtures Analysis Approaches

Aung

Ferguson

et al. 2021

Environ Health Perspect

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Background: Humans are exposed to mixtures of toxicants that can impact several biological pathways. We investigated the associations between multiple classes of toxicants and an extensive panel of biomarkers indicative of lipid metabolism, inflammation, oxidative stress, and angiogenesis. Methods: We conducted a cross-sectional study of 173 participants (median 26 wk gestation) from the LIFECODES birth cohort. We measured exposure analytes of multiple toxicant classes [metals, phthalates, phenols, and polycyclic aromatic hydrocarbons (PAHs)] in urine samples. We also measured endogenous biomarkers (eicosanoids, cytokines, angiogenic markers, and oxidative stress markers) in either plasma or urine. We estimated pair-wise associations between exposure analytes and endogenous biomarkers using multiple linear regression after adjusting for covariates. We used adaptive elastic net regression, hierarchical Bayesian kernel machine regression, and sparse-group LASSO regression to evaluate toxicant mixtures associated with individual endogenous biomarkers. Results: After false-discovery adjustment ( ), single-pollutant models yielded 19 endogenous biomarker signals associated with phthalates, 13 with phenols, 17 with PAHs, and 18 with trace metals. Notably, adaptive elastic net revealed that phthalate metabolites were selected for several positive signals with the cyclooxygenase ( ), cytochrome p450 ( ), and lipoxygenase ( ) pathways. Conversely, the toxicant classes that exhibited the greatest number of negative signals overall in adaptive elastic net were phenols ( ) and metals ( ). Discussion: This study characterizes cross-sectional endogenous biomarker signatures associated with individual and mixtures of prenatal toxicant exposures. These results can help inform the prioritization of specific pairs or clusters of endogenous biomarkers and exposure analytes for investigating health outcomes. https://doi.org/10.1289/EHP7396

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Asymmetric Synthesis of Methoxylated Ether Lipids: Total Synthesis of n-3 Polyunsaturated Docosahexaenoic Acid-Like Methoxylated Ether Lipid

et al. 2022

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The first total synthesis of a docosahexaenoic acid (DHA)-like methoxylated ether lipid (MEL) is reported. This compound constitutes an all-cis methylene skipped hexaene framework identical to that present in DHA, the well-known omega-3 polyunsaturated fatty acid. The polyene C22 hydrocarbon chain, bearing a methoxyl group in the 2-position and Rconfiguration at the resulting chiral center, is attached by an ether linkage to the pro-S hydroxymethyl group (sn-1 position) of a glycerol backbone. The asymmetric synthesis is highly convergent and based on the polyacetylene approach involving iterative copper-promoted coupling reactions of propargyl bromides with terminal alkynes and semihydrogenation of the resulting hexayne. Starting from enantiopure R-solketal and racemic epichlorohydrin, the targeted MEL was accomplished in an 8.2% yield over eight steps (longest linear sequence) involving an enantio-and diastereopure glyceryl glycidyl ether key C6-building blocks from which the polyynes were constructed.

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Synthesis of cyclooxygenase metabolites of 8,9-epoxyeicosatrienoic acid (EET): 11- and 15-hydroxy 8,9-EETs

Abstract: COX metabolites of 8,9-EET, previously observed as potent mitogenic lipid mediators, were synthesized for the first time by using two synthetic approaches. These synthetic materials allow for structural confirmation of COX metabolites of 8,9-EET and further study of their biological roles.

Cited by 6 publications

References 36 publications

Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2

Epoxyeicosatrienoic acid (EET)-stimulated angiogenesis is mediated by epoxy hydroxyeicosatrienoic acids (EHETs) formed from COX-2

Cross-Sectional Estimation of Endogenous Biomarker Associations with Prenatal Phenols, Phthalates, Metals, and Polycyclic Aromatic Hydrocarbons in Single-Pollutant and Mixtures Analysis Approaches

Asymmetric Synthesis of Methoxylated Ether Lipids: Total Synthesis of n-3 Polyunsaturated Docosahexaenoic Acid-Like Methoxylated Ether Lipid

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