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National Institute of Environmental Health Sciences

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Publication Detail

Title: Identification of 15-hydroxy-11,12-epoxyeicosatrienoic acid as a vasoactive 15-lipoxygenase metabolite in rabbit aorta.

Authors: Chawengsub, Yuttana; Aggarwal, Nitin T; Nithipatikom, Kasem; Gauthier, Kathryn M; Anjaiah, Siddam; Hammock, Bruce D; Falck, John R; Campbell, William B

Published In Am J Physiol Heart Circ Physiol, (2008 Mar)

Abstract: Arachidonic acid (AA) causes endothelium-dependent smooth muscle hyperpolarizations and relaxations that are mediated by a 15-lipoxygenase-I (15-LO-I) metabolite, 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA). We propose that AA is metabolized sequentially by 15-LO-I and hydroperoxide isomerase to an unidentified hydroxyepoxyeicosatrienoic acid (HEETA), which is hydrolyzed by a soluble epoxide hydrolase (sEH) to 11,12,15-THETA. After incubation of aorta with 14C-labeled AA, metabolites were extracted and the HEETAs were resolved by performing HPLC. Mass spectrometric analyses identified 15-Hydroxy-11,12-epoxyeicosatrienoic acid (15-H-11,12-EETA). Incubation of aortic incubates with methanol and acetic acid trapped the acid-sensitive 15-H-11,12-EETA as methoxydihydroxyeicosatrienoic acids (MDHEs) (367 m/z, M-H). Pretreatment of the aortic tissue with the sEH inhibitor 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA; 10(-6) M) increased the formation of 15-H-11,12-EETA, measured as MDHEs. Thus 15-H-11,12-EETA is an acid- and sEH-sensitive precursor of 11,12,15-THETA. Aortic homogenates and endothelial cells contain a 57-kDa protein corresponding to the rabbit sEH. In preconstricted aortic rings, AA (10(-7)-10(-4) M) and acetylcholine (10(-9)-10(-6) M) caused concentration-related relaxations that were enhanced by pretreatment with AUDA. These enhanced relaxations were inhibited by increasing extracellular [K(+)] from 4.8 to 20 mM. AA (3 x 10(-6) M) induced cell membrane hyperpolarization (from -31.0 +/- 1 to -46.8 +/- 2 mV) in aortic strips with an intact endothelium, which was enhanced by AUDA. These results indicate that 15-H-11,12-EETA is produced by the aorta, hydrolyzed by sEH to 11,12,15-THETA, and mediates relaxations by membrane hyperpolarization. 15-H-11,12-EETA represents an endothelium-derived hyperpolarizing factor.

PubMed ID: 18192225 Exiting the NIEHS site

MeSH Terms: 8,11,14-Eicosatrienoic Acid/analogs & derivatives*; 8,11,14-Eicosatrienoic Acid/chemistry; 8,11,14-Eicosatrienoic Acid/metabolism; Acetylcholine/metabolism; Animals; Aorta, Thoracic/metabolism*; Arachidonate 15-Lipoxygenase/metabolism*; Arachidonic Acids/metabolism; Blotting, Western; Chromatography, High Pressure Liquid; Epoxide Hydrolases/metabolism; Gas Chromatography-Mass Spectrometry; Membrane Potentials/physiology; Rabbits

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