5-Oxo-ETE is a major oxidative stress-induced arachidonate metabolite in B lymphocytes

Grant, Gail E.; Gravel, Sylvie; Guay, J.; Patel, Pranav; Mazer, Bruce; Rokach, Joshua; Powell, William S.

doi:10.1016/j.freeradbiomed.2011.02.010

Cited by 15 publications

(15 citation statements)

References 41 publications

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“…Therefore, 15-PGDH has two quite distinct properties: it can either inactivate PGs or activate HETEs to oxo-ETEs that exert a paracrine effect on endothelial cells (Figure 1). 11-Oxo-ETE, a member of the oxo-ETE family, 39−41 was observed previously as an endogenously derived lipid in human atherosclerotic plaques. (42) However, the biosynthesis of 11-oxo-ETE and its biological activity were not evaluated in that study.…”

Section: Discussionmentioning

confidence: 95%

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11-Oxoeicosatetraenoic Acid Is a Cyclooxygenase-2/15-Hydroxyprostaglandin Dehydrogenase-Derived Antiproliferative Eicosanoid

Liu

Zhang

Arora

et al. 2011

Chem. Res. Toxicol.

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Previously, we established that 11(R)-hydroxy-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (HETE) was a significant cyclooxygenase (COX)-2-derived arachidonic acid (AA) metabolite in epithelial cells. Stable isotope dilution chiral liquid chromatography (LC)-electron capture atmospheric pressure chemical ionization (ECAPCI)/mass spectrometry (MS) was used to quantify COX-2-derived eicosanoids in the human colorectal adenocarcinoma (LoVo) epithelial cell line, which expresses both COX-2 and 15-hydroxyprostaglandin dehydrogenase (15-PGDH). 11(R)-HETE secretion reached peak concentrations within minutes after AA addition before rapidly diminishing, suggesting further metabolism had occurred. Surprisingly, recombinant 15-PGDH, which is normally specific for oxidation of eicosanoid 15(S)-hydroxyl groups, was found to convert 11(R)-HETE to 11-oxo-5,8,12,14-(Z,Z,E,Z)-eicosatetraenoic acid (ETE). Furthermore, LoVo cell lysates converted 11(R)-HETE to 11-oxo-ETE and inhibition of 15-PGDH with 5-[[4-(ethoxycarbonyl)phenyl]azo]-2-hydroxy-benzeneacetic acid (CAY10397) (50 μM) significantly suppressed endogenous 11-oxo-ETE production with a corresponding increase in 11(R)-HETE. These data confirmed COX-2 and 15-PGDH as enzymes responsible for 11-oxo-ETE biosynthesis. Finally, addition of AA to the LoVo cells resulted in rapid secretion of 11-oxo-ETE into the media, reaching peak levels within 20 min of starting the incubation. This was followed by a sharp decrease in 11-oxo-ETE levels. Glutathione (GSH) S-transferase (GST) was found to metabolize 11-oxo-ETE to the 11-oxo-ETE-GSH (OEG)-adduct in LoVo cells, as confirmed by LC–MS/MS analysis. Bromodeoxyuridine (BrdU)-based cell proliferation assays in human umbilical vein endothelial cells (HUVECs) revealed that the half-maximal inhibitory concentration (IC50) of 11-oxo-ETE for inhibition of HUVEC proliferation was 2.1 μM. These results show that 11-oxo-ETE is a novel COX-2/15-PGDH-derived eicosanoid, which inhibits endothelial cell proliferation with a potency that is similar to that observed for 15d-PGJ2.

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Section: Discussionmentioning

confidence: 95%

“…(38) Similarly 5-lipoxygenase-derived 5( S )-HETE is metabolized by 5-hydroxyeicosanoid dehydrogenase into the chemoattractant 5-oxo-ETE. (39) Therefore, the oxoeicosanoids represent a family of oxidized lipids with diverse biological activities.…”

Section: Discussionmentioning

confidence: 99%

11-Oxoeicosatetraenoic Acid Is a Cyclooxygenase-2/15-Hydroxyprostaglandin Dehydrogenase-Derived Antiproliferative Eicosanoid

Liu

Zhang

Arora

et al. 2011

Chem. Res. Toxicol.

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“…Indeed, B-lymphocytes are able to produce the major 5-LOX metabolites 5-HETE and LTB 4 in the presence of exogenous arachidonic acid and oxidative stress (Jakobsson et al 1995). Grant et al (2011) showed that the more biological active 5-oxoETE was produced in human B lymphocyte cell lines from its precursor 5-HETE after subjection to oxidative stress by H 2 O 2 . These findings suggest the ability of PM to induce oxidative stress by producing reactive oxygen species (ROS), which might stimulate the production of 5-HETE and 5-oxoETE in different types of leukocytes, reflecting a higher inflammatory state.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Cord Blood Oxylipins and Exposure to Particulate Matter in the Early-Life Environment: An ENVIR ON AGE Birth Cohort Study

Martens

Gouveia

Madhloum

et al. 2017

Environ Health Perspect

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Background:As part of the lipidome, oxylipins are bioactive lipid compounds originating from oxidation of different fatty acids. Oxylipins could provide a new target in the developmental origins model or the ability of early life exposure to change biology.Objectives:We studied the association between in utero PM2.5 (particulate matter with aerodynamic diameter < 2.5 μm) exposure and oxylipin profiles in newborns.Methods:Thirty-seven oxylipins reflecting the cyclooxygenase (COX), lipoxygenase (5-LOX and 12/15-LOX), and cytochrome P450 (CYP) pathways were assayed in 197 cord blood plasma samples from the ENVIRONAGE birth cohort. Principal component (PC) analysis and multiple regression models were used to estimate associations of in utero PM2.5 exposure with oxylipin pathways and individual metabolites.Results:A principal component representing the 5-LOX pathway (6 metabolites) was significantly positively associated with PM2.5 exposure during the entire (multiple testing–adjusted q-value = 0.05) and second trimester of pregnancy (q = 0.05). A principal component representing the 12/15-LOX pathway (11 metabolites) was positively associated with PM2.5 exposure during the second trimester of pregnancy (q = 0.05). PM2.5 was not significantly associated with the COX pathway during any time period. There was a positive but nonsignificant association between second-trimester PM2.5 and the CYP pathway (q = 0.16).Conclusion: In utero exposure to particulate matter, particularly during the second trimester, was associated with differences in the cord blood levels of metabolites derived from the lipoxygenase pathways. These differences may indicate an effect of air pollution during in utero life on the inflammatory state of the newborn at birth. Oxylipins may be important mediators between early life exposures and health outcomes later in life.Citation:Martens DS, Gouveia S, Madhloum N, Janssen BG, Plusquin M, Vanpoucke C, Lefebvre W, Forsberg B, Nording M, Nawrot TS. 2017. Neonatal cord blood oxylipins and exposure to particulate matter in the early-life environment: an ENVIRONAGE birth cohort study. Environ Health Perspect 125:691–698; http://dx.doi.org/10.1289/EHP291

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“…In B cells, 5-oxo-ETE is a major product of AA metabolism which accumulates as a result of oxidative stress. 5-oxo-ETE production is promoted through increased AA production and also increasing levels of NADP+, a cofactor for 5-HEDH [41]. Furthermore, 5-oxo-ETE production is associated with cell survival after treatment with cytotoxic agents in prostate cancer cells [42], [43].…”

Section: Discussionmentioning

confidence: 99%

Cell Survival Signalling through PPARδ and Arachidonic Acid Metabolites in Neuroblastoma

et al. 2013

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Retinoic acid (RA) has paradoxical effects on cancer cells: promoting cell death, differentiation and cell cycle arrest, or cell survival and proliferation. Arachidonic acid (AA) release occurs in response to RA treatment and, therefore, AA and its downstream metabolites may be involved in cell survival signalling. To test this, we inhibited phospholipase A2-mediated AA release, cyclooxygenases and lipoxygenases with small-molecule inhibitors to determine if this would sensitise cells to cell death after RA treatment. The data suggest that, in response to RA, phospholipase A2-mediated release of AA and subsequent metabolism by lipoxygenases is important for cell survival. Evidence from gene expression reporter assays and PPARδ knockdown suggests that lipoxygenase metabolites activate PPARδ. The involvement of PPARδ in cell survival is supported by results of experiments with the PPARδ inhibitor GSK0660 and siRNA-mediated knockdown. Quantitative reverse transcriptase PCR studies demonstrated that inhibition of 5-lipoxygenase after RA treatment resulted in a strong up-regulation of mRNA for PPARδ2, a putative inhibitory PPARδ isoform. Over-expression of PPARδ2 using a tetracycline-inducible system in neuroblastoma cells reduced proliferation and induced cell death. These data provide evidence linking lipoxygenases and PPARδ in a cell survival-signalling mechanism and suggest new drug-development targets for malignant and hyper-proliferative diseases.

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5-Oxo-ETE is a major oxidative stress-induced arachidonate metabolite in B lymphocytes

Cited by 15 publications

References 41 publications

11-Oxoeicosatetraenoic Acid Is a Cyclooxygenase-2/15-Hydroxyprostaglandin Dehydrogenase-Derived Antiproliferative Eicosanoid

11-Oxoeicosatetraenoic Acid Is a Cyclooxygenase-2/15-Hydroxyprostaglandin Dehydrogenase-Derived Antiproliferative Eicosanoid

Neonatal Cord Blood Oxylipins and Exposure to Particulate Matter in the Early-Life Environment: An ENVIR ON AGE Birth Cohort Study

Cell Survival Signalling through PPARδ and Arachidonic Acid Metabolites in Neuroblastoma

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