Formation of 9-Hydroxyoctadecadienoic Acid from Linoleic Acid in Endothelial Cells

Kaduce, Terry L.; Figard, Paul H.; Leifur, R; Spector, Arthur A.

doi:10.1016/s0021-9258(18)83504-9

Cited by 85 publications

(18 citation statements)

References 41 publications

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“…In this thesis, the data indicates that 9-HODE is produced differently as 13-HODE, in fact mainly by COX-2 and 12-LOX [133,135]. This is in good agreement with earlier findings, hypothesizing a COX involvement and products of 12-LOX involved in TRPV1 sensitization [219,220]. Thus, the elevated 9-HODE levels might be connected to mechanical hypersensitivity, since it binds to its receptor G2A and by this sensitizes TRPV1 in primary sensory neurons, which is known to be responsible for pain perception [85,180,221].…”

Section: G2a In the Crosstalk Of Immune Cells And Primary Sensory Neurons During Acute Phase Of Trauma Induced Neuropathiessupporting

confidence: 90%

Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

Osthues¹

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Neuropathic pain, a form of chronic pain, is a steadily rising health problem due to health costs and increasing numbers of patients. Neuropathic pain conditions arise upon metabolic disorders, infections, chemotherapeutic treatment, trauma or nerve injury. Especially nerve injury induced neuropathic pain is characterized by spontaneous or ongoing pain due to neuroimmune interactions. Thereby, inflammatory mediators, released by the injured nerve, recruit to and activate immune cells at the site of injury. Those mediators further activate transient receptor potential vanilloid 1 (TRPV1), a known channel involved in pain perception, or bind to G-protein coupled receptors (GPCR) in peripheral nerve endings. The following activated second messenger signaling pathways lead to sensitization of TRPV1. One of those GPCRs is G2A. The overall aim of this thesis was to investigate the role of G2A in nerve-injury induced neuropathic pain. For this, the common mouse model of nerve-injury induced neuropathic pain, the spared-nerve injury, was used. As measurements with dynamic plantar aesthesiometer showed, G2A-deficiency leads to reduced mechanical hypersensitivity. Upon analysis with FACS, ELISA and Luminex a reduced number of macrophages and neutrophils at the injured nerve, as well as less inflammatory mediators (TNFα, IL-6, VEGF) in G2A-deficient animals was observed. In dorsal root ganglia (DRGs) there was only a reduced number of macrophages and less IL-12 observed in G2A-deficient animals. Additionally, in wild-type mice, G2A agonist 9-HODE was elevated at the injured nerve, as a LC-MS/MS analysis showed. To investigate the underlying pathways of G2A-9-HODE signaling, a proteom screen was performed. This screen revealed upregulation of multiple proteins involved in migration in wild-type macrophages. Additionally, Ca-Imaging and transwell migration assays showed that the G2A antagonist G2A11, had desensitizing effects on DRG neurons and inhibited macrophage migration. Overall, the results suggest that loss of G2A has dual effects. On the one hand loss of G2A is antinociceptive. On the other hand, G2A-deficiency leads to reduced inflammation, suggesting G2A as promising target in treatment of neuropathic pain. Here, an antagonist had inhibitory effects on the migration and the sensitization.

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Section: G2a In the Crosstalk Of Immune Cells And Primary Sensory Neurons During Acute Phase Of Trauma Induced Neuropathiessupporting

confidence: 90%

Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

Osthues¹

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“…The flow rate was 0.9 mL per min. Radioactivity was measured by combining the column effluent with liquid scintillation solution and passing the mixture through an on-line Radiomatic Flo-One Beta detector (30,31).…”

Section: Lipid Analysismentioning

confidence: 99%

“…An aliquot of this extract was dried under N 2 , liquid scintillation counting solution was added, and the radioactivity was assayed with a Packard 4640 liquid scintillation spectrometer. Quenching was monitored with a 226 Ra external standard (30,31).…”

Section: Lipid Analysismentioning

confidence: 99%

“…To identify the unknown metabolites, the hydrolyzed cell or medium lipid extracts were methylated by incubation for 10 min at 22 Њ C with freshly prepared ethereal diazomethane, and the resulting methyl esters were acetylated with acetic anhydride by refluxing with pyridine for 1 h at 70 Њ C (27,28,30,34). These derivatives were separated by HPLC (27,28).…”

Section: Identification Of Hode Metabolitesmentioning

confidence: 99%

“…For gas chromatography and mass spectrometry (GC/MS) analysis, trimethylsilylether derivatives of the methyl esters were prepared by incubation for 1 h at 60 Њ C with 50 L bis(trimethylsilyl)trifluoroacetamide containing 1% trimethylchlorosilane. GC/MS analysis was done with a Hewlett-Packard 5890 gas chromatograph equipped with a 0.32 mm ϫ 15 m DB-1 column ( J & W Scientific) (27,28,30,34). The on-column and transfer line were heated to 250 Њ C, and the oven was maintained at 160 Њ C for 5 min and then ramped to 250 Њ C at a rate of 5 Њ C per min.…”

Section: Identification Of Hode Metabolitesmentioning

confidence: 99%

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13-(S)-Hydroxyoctadecadienoic acid (13-HODE) incorporation and conversion to novel products by endothelial cells

Fang

Kaduce

Spector

1999

Journal of Lipid Research

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13(S)-Hydroxy-[12,13-3 H]octadecadienoic acid (13-HODE), a linoleic acid oxidation product that has vasoactive properties, was rapidly taken up by bovine aortic endothelial cells. Most of the 13-HODE was incorporated into phosphatidylcholine, and 80% was present in the sn -2 position. The amount of 13-HODE retained in the cells gradually decreased, and radiolabeled metabolites with shorter reverse-phase high-performance liquid chromatography retention times (RT) than 13-HODE accumulated in the extracellular fluid. The three major metabolites were identified by gas chromatography combined with mass spectrometry as 11-hydroxyhexadecadienoic acid (11-OH-16:2), 9-hydroxytetradecadienoic acid (9-OH-14:2), and 7-hydroxydodecadienoic acid (7-OH-12:2). Most of the radioactivity contained in the cell lipids remained as 13-HODE. However, some 11-OH-16:2 and several unidentified products with longer RT than 13-HODE were detected in the cell lipids. Normal human skin fibroblasts also converted 13-HODE to the three major chain-shortened metabolites, but Zellweger syndrome fibroblasts produced only a very small amount of 11-OH-16:2. Therefore, the chain-shortened products probably are formed primarily by peroxisomal ␤ -oxidation. These findings suggest that peroxisomal ␤ -oxidation may constitute a mechanism for the inactivation and removal of 13-HODE from the vascular wall. Because this is a gradual process, some 13-HODE that is initially incorporated remains in endothelial phospholipids, especially phosphatidylcholine. This may be the cause of some of the functional perturbations produced by 13-HODE in the vascular wall. -Fang, X., T. L. Kaduce, and A. A. Spector. 13-(S)-Hydroxyoctadecadienoic acid (13-HODE) incorporation and conversion to novel products by endothelial cells.

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Oxygenated metabolites of polyunsaturated fatty acids: Formation and function in blood and vascular cells

Lagarde

2010

Euro J Lipid Sci & Tech

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Unsaturated fatty acids esterified in glycerophospholipids are abundant components of cell membranes. They can be released by phospholipases, and subsequently converted into oxygenated derivatives by diverse cyclooxygenase, lipoxygenase and/or cytochrome P 450 enzymes. The best known products, i.e. prostanoids, hydroxylated dienes, trienes, and tetraenes, as well as epoxides, are frequently released and act on blood and vascular cells. The present paper briefly reviews these different aspects, pointing out recent developments in the field of docosanoids produced from docosahexaenoic acid.Practical applications: Polyunsaturated fatty acids (PUFA) are highly oxidizable with multiple possibilities of autoxidation and enzyme-dependent oxygenation. The present review aims at providing a short and comprehensive overview of the biosynthesis of the main oxygenated products derived from 18, 20, and 22 carbon PUFA with their relevant function in the vascular system. The so-called octadecanoids, eicosanoids, and docosanoids, respectively, are selected among the numerous isomers because of their recognized biological activities.

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Formation of 9-Hydroxyoctadecadienoic Acid from Linoleic Acid in Endothelial Cells

Cited by 85 publications

References 41 publications

Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

Oxidized lipids and signaling pathways of G2A receptor involved in nerve injury induced neuropathic pain

13-(S)-Hydroxyoctadecadienoic acid (13-HODE) incorporation and conversion to novel products by endothelial cells

Oxygenated metabolites of polyunsaturated fatty acids: Formation and function in blood and vascular cells

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