Hydrolysis of<i>cis</i>- and<i>trans-</i>Epoxyeicosatrienoic Acids by Rat Red Blood Cells

Jiang, Houli; Zhu, Angela; Mamczur, Magdalena; Morisseau, Christophe; Hammock, Bruce D.; Falck, John R.; McGiff, John C.

doi:10.1124/jpet.107.134858

Cited by 30 publications

(59 citation statements)

References 39 publications

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“…14,15-and 11,12-EET are metabolized by sEH to 14,15-and 11,12-DHET, respectively, and this metabolism results in a loss of biological activity (45 (45,57). Thus, inhibition of sEH will increase both cis-and trans-EETs and decrease the DHETs.…”

Section: Discussionmentioning

confidence: 99%

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GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein-coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC 50 = 0.58 ± 0.08 µM, 0.91 ± 0.08 µM, 3.9 ± 0.06 µM and 19 ± 0.37 nM, respectively). EETs with cisand trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12-and 14,15-vicdihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET-and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAP kinase inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EETinduced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation. INTRODUCTIONhttp://www.jbc.org/cgi

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Section: Discussionmentioning

confidence: 99%

“…The cis-and trans-11,12-and -14,15-EETs were equally potent in stimulating GPR40. Cis-and trans-EET have been measured in the plasma and red blood cells and relax rat renal arcuate arteries equally (57,58). In contrast, the cis-14,15-EET was more potent than the trans-isomer in relaxing bovine coronary arteries (59).…”

Section: Discussionmentioning

confidence: 99%

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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“…EET and DHET extraction for electrospray ionization (ESI)/LC/MS analyses were performed as described previously. 35 In brief, a Finnigan LCQ Advantage quadrupole ion-trap MS (Thermo Fisher Scientific) equipped with ESI source run by Xcalibur software was used. Reversed-phase HPLC was run with a Luna C18(2) 250 ϫ 2.0-mm column (Phenomenex, Torrance, CA) maintained at 30°C with an isocratic eluent of acetonitrile/water/methanol/acetic acid (60:30:10:0.05) at a flow rate of 0.30 ml/min.…”

Section: Assay For Seh Activitymentioning

confidence: 99%

High Potassium Intake Enhances the Inhibitory Effect of 11,12-EET on ENaC

Sun

Lin

Yue

et al. 2010

Journal of the American Society of Nephrology

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High dietary potassium stimulates the renal expression of cytochrome P450 (CYP) epoxygenase 2C23, which metabolizes arachidonic acid (AA). Because the AA metabolite 11,12-epoxyeicosatrienoic acid (11, can inhibit the epithelial sodium channel (ENaC) in the cortical collecting duct, we tested whether dietary potassium modulates ENaC function. High dietary potassium increased 11,12-EET in the isolated cortical collecting duct, an effect mimicked by inhibiting the angiotensin II type I receptor with valsartan. In patch-clamp experiments, a high potassium intake or treatment with valsartan enhanced AA-induced inhibition of ENaC, an effect mediated by a CYP-epoxygenase-dependent pathway. Moreover, high dietary potassium and valsartan each augmented the inhibitory effect of 11,12-EET on ENaC. Liquid chromatography/mass spectrometry showed that the rate of EET conversion to dihydroxyeicosatrienoic acids (DHET) was lower in renal tissue obtained from rats on a high-potassium diet than from those on a control diet, but this was not a result of altered expression of soluble epoxide hydrolase (sEH). Instead, suppression of sEH activity seemed to be responsible for the 11,12-EET-mediated enhanced inhibition of ENaC in animals on a high-potassium diet. Patch-clamp experiments demonstrated that 11,12-DHET was a weak inhibitor of ENaC compared with 11,12-EET, whereas 8,9-and 14,15-DHET were not. Furthermore, inhibition of sEH enhanced the 11,12-EET-induced inhibition of ENaC similar to high dietary potassium. In conclusion, high dietary potassium enhances the inhibitory effect of AA and 11,12-EET on ENaC by increasing CYP epoxygenase activity and decreasing sEH activity, respectively. 21: 166721: -167721: , 201021: . doi: 10.1681 We previously demonstrated that cytochrome P450 (CYP) epoxygenase-dependent arachidonic acid (AA) metabolism inhibited epithelial sodium channel (ENaC) in the cortical collecting duct (CCD) and that 11,12-epoxyeicosatrienoic acid (11,12-EET) was responsible for mediating the effect of AA on ENaC. 1 Furthermore, the observation that AA failed to inhibit ENaC in the CCD of the mice with a low expression of CYP2C44 suggests that CYP2C44 and its orthologs may be responsible for mediating the inhibitory effect of AA. 2 The expression of CYP2C44 or its orthologs has been shown to be regulated by dietary Na intake: A high Na intake stimulates 2 whereas a low Na intake suppresses the expression of CYP2C44 homologue. 3 A large body of evidence has suggested that EET plays a role in the regulation of renal Na transport and salt-sensitive hypertension. 1,2,4,5 Inhibition of CYP epoxygenase-dependent AA metabolism results in the development of salt-sensitive hypertension 5,6 ; however, the BP returned to normal after the removal of the epoxygenase inhibitor, even when the animals were still kept on a high-Na diet. The high Na intake-induced in- J Am Soc Nephrol

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“…Their key roles in drug discovery are virtual screening and de novo design, in silico ADMET prediction and advanced approaches for defining protein-ligand binding 1 . Epoxyeicosatrienoic acid (EET) is the epoxide metabolite of arachidonic acid, formed by the action of Cytochrome P450 epoxygenase in various organs including the liver, kidney and heart 4,5 . They possess many physiologically important roles like fibrinolytic, anti-thrombotic, anti-proliferative, vasodilatory, anti-inflammatory, bronchodilatory and anti-diabetic actions.…”

Section: Introductionmentioning

confidence: 99%

Design, Admet and Docking Studies on Some Novel Chalcone Derivatives as Soluble Epoxide Hydrolase Enzyme Inhibitors

Asokkumar

Tangella

Umamaheshwari

et al. 2012

J. Chil. Chem. Soc.

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Drug discovery is a lengthy and costly process which aims at bringing in a novel therapeutic molecule for the treatment of various diseases. In the present study, a novel series of eighty chalcone derivatives [(4-substituted)-(4'-substituted)-3' substituted sulphonyl (2E)-1,3-diphenylprop-2-en-1-one] were designed to inhibit soluble epoxide hydrolase enzyme (sEH). Lipinski's rule of 5 and absorption, distribution, metabolism, elimination and toxicity (ADMET) properties of the compounds were calculated using Molinspiration server and Accord for excel software respectively. All 80 compounds have passed the Lipinski's rule of 5 and only 20 compounds showed considerable ADMET properties. These 20 compounds were subjected to molecular docking studies using AutoDock 4.2 in order to rationalize the possible interactions between test compounds and the active site of human soluble epoxide hydrolase enzyme (1ZD3). Binding energy, intermolecular energy and inhibition constant were the main parameters taken into consideration in this study. The binding energies ranged from -6.07 to -7.89 kcal/mol, the inhibition constant ranging from 1.64 µM to 35.45 µM and intermolecular energy ranging between -9.38 kcal/mol to -6.97 kcal/mol. Hence, further pharmacophore optimization and in vivo studies are necessary to develop potent chemical entities that could inhibit the sEH enzyme.

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Hydrolysis ofcis- andtrans-Epoxyeicosatrienoic Acids by Rat Red Blood Cells

Cited by 30 publications

References 39 publications

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

High Potassium Intake Enhances the Inhibitory Effect of 11,12-EET on ENaC

Design, Admet and Docking Studies on Some Novel Chalcone Derivatives as Soluble Epoxide Hydrolase Enzyme Inhibitors

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