[40] Synthesis of epoxyeicosatrienoic acids and heteroatom analogs

Falck, J. R.; Yadagiri, Pendri; Capdevila, Jorge H.

doi:10.1016/0076-6879(90)87042-2

Cited by 55 publications

(38 citation statements)

References 14 publications

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“…Anti-rabbit horseradish peroxidase-conjugated IgG was obtained from Bio-Rad. Methyl-EETs were synthesized by oxidation of arachidonate methyl ester with meta-chloroperbenzoic acid (13) followed by ester hydrolysis in dilute base following the procedures of Falck et al (14). Regioisomeres were purified by a combination of open column and reverse-phase high performance liquid chromatography.…”

Section: Methodsmentioning

confidence: 99%

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Davis

Thompson

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

112

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Atherosclerosis, in its myriad incarnations the foremost killer disease in the industrialized world, is characterized by aberrant proliferation of vascular smooth muscle (VSM) cells in part as a result of the recruitment of inflammatory cells to the blood vessel wall. The epoxyeicosatrienoic acids are synthesized from arachidonic acid in a reaction catalyzed by the cytochrome P450 system and are vasoactive substances. Metabolism of these compounds by epoxide hydrolases results in the formation of compounds that affect the vasculature in a pleiotropic manner. As an outgrowth of our observations that urea inhibitors of the soluble epoxide hydrolase (sEH) reduce blood pressure in spontaneously hypertensive rats as well as the findings of other investigators that these compounds possess antiinflammatory actions, we have examined the effect of sEH inhibitors on VSM cell proliferation. We now show that the sEH inhibitor 1-cyclohexyl-3-dodecyl urea (CDU) inhibits human VSM cell proliferation in a dose-dependent manner and is associated with a decrease in the level of cyclin D1. In addition, cis-epoxyeicosatrienoic acid mimics the growth-suppressive activity of CDU; there is no evidence of cellular toxicity or apoptosis in CDU-treated cells when incubated with 20 μM CDU for up to 48 h. These results, in light of the antiinflammatory and antihypertensive properties of these compounds that have been demonstrated already, suggest that the urea class of sEH inhibitors may be useful for therapy for diseases such as hypertension and atherosclerosis characterized by exuberant VSM cell proliferation and vascular inflammation

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Section: Methodsmentioning

confidence: 99%

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Davis

Thompson

Howard

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

111

112

View full text Add to dashboard Cite

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“…Briefly, 8 ϫ 10 6 endothelial cells were frozen in liquid nitrogen and homogenized in 15 ml of phosphate-buffered saline containing triphenylphosphine (10 mg), and the homogenate was extracted under acidic conditions with two volumes of chloroform/methanol (2:1) and twice more with an equal volume of chloroform. The combined organic phases were evaporated in tubes containing mixtures of 1-14 C-labeled 8,9-, 11,12-, and 14,15-EET internal standards (57 Ci/mol; 30 ng each), which were synthesized from [1-14 C]arachidonic acid by nonselective epoxidation (18). Saponification to recover phospholipid-bound EETs was followed by silica column purification.…”

Section: Methodsmentioning

confidence: 99%

Activation of Gαs Mediates Induction of Tissue-type Plasminogen Activator Gene Transcription by Epoxyeicosatrienoic Acids

Node

Ruan

Dai

et al. 2001

Journal of Biological Chemistry

213

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The epoxyeicosatrienoic acids (EETs) are products of cytochrome P450 (CYP) epoxygenases that have vasodilatory and anti-inflammatory properties. Here we report that EETs have additional fibrinolytic properties. In vascular endothelial cells, physiological concentrations of EETs, particularly 11,12-EET, or overexpression of the endothelial epoxygenase, CYP2J2, increased tissue plasminogen activator (t-PA) expression by 2.5-fold without affecting plasminogen activator inhibitor-1 expression. This increase in t-PA expression correlated with a 4-fold induction in t-PA gene transcription and a 3-fold increase in t-PA fibrinolytic activity and was blocked by the CYP inhibitor, SKF525A, but not by the calcium-activated potassium channel blocker, charybdotoxin, indicating a mechanism that does not involve endothelial cell hyperpolarization. The t-PA promoter is cAMP-responsive, and induction of t-PA gene transcription by EETs correlated with increases in intracellular cAMP levels and, functionally, with cAMP-driven promoter activity. To determine whether increases in intracellular cAMP levels were due to modulation of guanine nucleotide-binding proteins, we assessed the effects of EETs on G␣ s and G␣ i2 . Treatment with EETs increased G␣ s , but not G␣ i2 , GTP-binding activity by 3.5-fold. These findings indicate that EETs possess fibrinolytic properties through the induction of t-PA and suggest that endothelial CYP2J2 may play an important role in regulating vascular hemostasis.

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“…After removing the solvent, the fatty acid was methylated with 12% BF 3 in methanol for 45 min at 50°C. Following extraction, the AA methyl ester was incubated with 3-chloroperoxybenzoic acid in methylene chloride for 1.5 h at 0°C (28). The reaction was stopped by addition of 50 l of methyl sulfide, and the mixture was allowed to stand at room temperature for 20 min.…”

Section: Synthesis Of [mentioning

confidence: 99%

“…The [ 3 H]EET methyl esters were isolated and purified by reverse-phase high performance liquid chromatography (HPLC) using a gradient that started at 65% acetonitrile, 35% water, was ramped to 85% acetonitrile, 15% water over 55 min, and then was taken to 100% acetonitrile at 60 min and held constant for 5 min. Fractions containing the purified [ 3 H]11,12-and 14,15-EET 2 methyl esters were hydrolyzed with 50 l of 2 N NaOH in 500 l of methanol at 50°C for 1 h, and the [ 3 H]EETs were extracted from the mixture with water-saturated ethyl acetate (28). After drying under N 2 , the [ 3 H]EETs were suspended in 95% ethanol and stored at Ϫ80°C.…”

Section: Synthesis Of [mentioning

confidence: 99%