Correction to: Bioconversion of arachidonic acid into human 14,15-hepoxilin B3 and 13,14,15-trioxilin B3 by recombinant cells expressing microbial 15-lipoxygenase without and with epoxide hydrolase

Objective: We have previously observed fatty acid epoxides, a class of potent anti-inflammatory oxylipins, in circulating VLDL. The source of these epoxides is unknown. Cytochrome P450 (CYP450) produces them via oxygenation of polyunsaturated fatty acids (PUFAs), and soluble epoxide hydrolase (sEH) converts them to diols. Our objectives were 1) to investigate if incorporation of epoxides into VLDL occurs via hepatic VLDL synthesis and 2) to determine if incorporation is modulated by inflammation or by inhibition of hepatic sEH. Approach and Results: A 2х2 factorial design was used for treatment assignment. Livers were isolated from rats treated with pro-inflammatory lipopolysaccharide (LPS, 10 mg/kg ip) or saline. AUDA, an inhibitor of sEH (10 μM), was included or excluded in the perfusate (Control, N=3; LPS, N=4; AUDA, N=4; LPS+AUDA, N=4). Livers were perfused for 180 minutes. VLDL was isolated by ultra-centrifugation, then analyzed by LC-MS/MS for oxylipin content. Analyzed epoxides and diols were derived from alpha-linolenic acid (ALA), linoleic acid (LA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Two-way ANOVA’s were used with triglyceride concentration as a covariate. Concentrations (nM) are reported as mean [95% CI]. DHA-derived epoxides increased with AUDA treatment (3.91 [3.01, 5.07]) compared to livers without AUDA (2.06 [1.58, 2.67]) (p=0.004), but other epoxides were unchanged by AUDA. EPA and ALA-derived epoxides decreased with LPS treatment (0.32 [0.22, 0.47]; 2.44 [2.07, 2.87]) compared to animals without LPS (0.73 [0.46, 1.16]; 3.28 [2.71, 3.96]) (p=0.01; 0.02). AA and DHA-derived diols decreased with LPS treatment (1.01 [0.82, 1.25]; 0.21 [0.17, 0.26]) compared to animals without LPS (1.46 [1.15, 1.86]; 0.31 [0.24, 0.39]) (p=0.03; 0.03). Conclusions: Treatment with LPS and AUDA have significant effects on incorporation of epoxides and diols into VLDL, supporting hepatic incorporation controlled by inflammation. Inflammation decreased select EPA- and ALA-derived epoxides. In contrast, sEH inhibition increased only DHA-derived epoxides. Surprisingly, in VLDL only epoxides derived from omega-3 fatty acids were affected by either inflammation or inhibition of sEH.

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Treatment of Primary Aldosteronism Increases Plasma Epoxyeicosatrienoic Acids

Hypertension ◽

10.1161/hypertensionaha.120.14808 ◽

2021 ◽

Vol 77 (4) ◽

pp. 1323-1331

Author(s):

James M. Luther ◽

Dawei S. Wei ◽

Kakali Ghoshal ◽

Dungeng Peng ◽

Gail K. Adler ◽

...

Keyword(s):

Adipose Tissue ◽

Arachidonic Acid ◽

Primary Aldosteronism ◽

Epoxide Hydrolase ◽

Prolonged Exposure ◽

Soluble Epoxide Hydrolase ◽

Molar Ratio ◽

Epoxyeicosatrienoic Acids ◽

Unilateral Adrenalectomy ◽

Mineralocorticoid Antagonist

Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules formed from arachidonic acid by the action of CYP450s. EETs cause vasodilation, exert anti-inflammatory effects, and enhance insulin secretion and sensitivity in rodents. EETs are metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH (soluble epoxide hydrolase), and 14,15-DHET has been reported to be increased in patients with primary aldosteronism, but the effects of aldosterone on EET concentrations and sEH activity are unknown. We tested the hypothesis that treatment of primary aldosteronism would alter EET concentrations in humans. We studied 9 patients with primary aldosteronism before and at least 3 months after unilateral adrenalectomy (6) or treatment with a mineralocorticoid antagonist (3). Circulating total EET concentrations increased to 18.5±12.6 from 11.9±5.9 nmol/L with treatment of primary aldosteronism ( P =0.027). Among the regioisomers of EETs, 14,15-EET significantly increased after treatment, whereas 11,12-EET and 8,9 EET were unaltered. Total DHET concentrations and specific regioisomers of DHET did not change significantly. Circulating total EETs (ρ=−0.52, P =0.026), 14,15-EET ( ρ =−0.56, P =0.015), and 11,12-EET ( ρ =−0.48, P =0.042) correlated inversely with aldosterone. We also assessed EETs after a 12-hour aldosterone or vehicle infusion in a randomized cross-over study in healthy volunteers. Plasma EETs were similar after 12-hour aldosterone or vehicle infusion. Lastly, 3-day infusion of aldosterone in mice decreased EET concentrations in adipose and muscle and increased sEH expression as determined by molar ratio of DHETs to EETs and soluble epoxide hydrolase ( Ephx2 ) mRNA expression in adipose tissue. These studies suggest that prolonged exposure to increased aldosterone decreases EET concentrations.

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High K (HK) intake enhances the inhibitory effect of Arachidonic Acid (AA) to ENaC by stimulating CYP Epoxygenase and inhibiting soluble Epoxide Hydrolase (sEH)

The FASEB Journal ◽

10.1096/fasebj.23.1_supplement.998.10 ◽

2009 ◽

Vol 23 (S1) ◽

Author(s):

Peng Sun ◽

Wenhui Wang

Keyword(s):

Arachidonic Acid ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Inhibitory Effect ◽

High K

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Modulation of Arachidonic Acid Metabolism in the Rat Kidney by Sulforaphane: Implications for Regulation of Blood Pressure

ISRN Pharmacology ◽

10.1155/2014/683508 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Fawzy Elbarbry ◽

Anke Vermehren-Schmaedick ◽

Agnieszka Balkowiec

Keyword(s):

Blood Pressure ◽

Drinking Water ◽

Arachidonic Acid ◽

Epoxide Hydrolase ◽

Rat Kidney ◽

Soluble Epoxide Hydrolase ◽

Arachidonic Acid Metabolism ◽

Dependent Manner ◽

Shr Rats ◽

Arterial Blood

Background. We investigated the effects of sulforaphane (SF), the main active isothiocyanate in cruciferous vegetables, on arachidonic acid (AA) metabolism in the kidney and its effect on arterial blood pressure, using spontaneously hypertensive rats (SHR) as models. Methods. Rats were treated for 8 weeks with either drinking water alone (control) or SF (20 or 40 mg/kg) added to drinking water. Mean arterial pressure (MAP) was measured at 7-day intervals throughout the study. At the end of treatment rats were euthanized, and kidneys were harvested to prepare microsomes and measure enzymes involved in regulation of vasoactive metabolites: CYP4A, the key enzyme in the formation of 20-hydroxyeicosatetraenoic acid, and the soluble epoxide hydrolase, which is responsible for the degradation of the vasodilator metabolites such as epoxyeicosatetraenoic acids. Effect of SF on kidney expression of CYP4A was investigated by immunoblotting. Results. We found that treatment with SF leads to significant reductions in both, the expression and activity of renal CYP4A isozymes, as well as the activity of soluble epoxide hydrolase (sEH). Consistent with these data, we have found that treatment with SF resisted the progressive rise in MAP in the developing SHR in a dose-dependent manner. Conclusion. This is the first demonstration that SF modulates the metabolism of AA by both P450 enzymes and sEH in SHR rats. This may represent a novel mechanism by which SF protects SHR rats against the progressive rise in blood pressure.

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Epoxide hydrolases regulate epoxyeicosatrienoic acid incorporation into coronary endothelial phospholipids

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.5.h2098 ◽

1999 ◽

Vol 277 (5) ◽

pp. H2098-H2108 ◽

Cited By ~ 27

Author(s):

Neal L. Weintraub ◽

Xiang Fang ◽

Terry L. Kaduce ◽

Mike VanRollins ◽

Papri Chatterjee ◽

...

Keyword(s):

Arachidonic Acid ◽

Epoxide Hydrolase ◽

Epoxyeicosatrienoic Acids ◽

Epoxyeicosatrienoic Acid ◽

Epoxide Hydrolases ◽

Porcine Coronary Artery ◽

A 23187 ◽

Acid Incorporation ◽

Cytochrome P 450 ◽

Endothelium Dependent Relaxation

Cytochrome P-450-derived epoxyeicosatrienoic acids (EETs) are avidly incorporated into and released from endothelial phospholipids, a process that results in potentiation of endothelium-dependent relaxation. EETs are also rapidly converted by epoxide hydrolases to dihydroxyeicosatrienoic acid (DHETs), which are incorporated into phospholipids to a lesser extent than EETs. We hypothesized that epoxide hydrolases functionally regulate EET incorporation into endothelial phospholipids. Porcine coronary artery endothelial cells were treated with an epoxide hydrolase inhibitor, 4-phenylchalcone oxide (4-PCO, 20 μmol/l), before being incubated with 3H-labeled 14,15-EET (14,15-[3H]EET). 4-PCO blocked conversion of 14,15-[3H]EET to 14,15-[3H]DHET and doubled the amount of radiolabeled products incorporated into cell lipids, with >80% contained in phospholipids. Moreover, pretreatment with 4-PCO before incubation with 14,15-[3H]EET enhanced A-23187-induced release of radiolabeled products into the medium. In contrast, 4-PCO did not alter uptake, distribution, or release of [3H]arachidonic acid. In porcine coronary arteries, 4-PCO augmented 14,15-EET-induced potentiation of endothelium-dependent relaxation to bradykinin. These data suggest that epoxide hydrolases may play a role in regulating EET incorporation into phospholipids, thereby modulating endothelial function in the coronary vasculature.

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