Pathways of Epoxyeicosatrienoic Acid Metabolism in Endothelial Cells

Fang, Xiang; Kaduce, Terry L.; Weintraub, Neal L.; Harmon, Shawn D.; Teesch, Lynn M.; Morisseau, Christophe; Thompson, David A.; Hammock, Bruce D.; Spector, Arthur A.

doi:10.1074/jbc.m011761200

Cited by 177 publications

(58 citation statements)

References 42 publications

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“…The sEH functions in vivo to metabolize EETs to their corresponding dihydroxy derivatives (29). This enzyme, which represents a single known and highly conserved gene product with over 90% homology between rodent and human (30), can be inhibited selectively and competitively in vitro by a variety of urea, carbamate, and amide derivatives (16,18).…”

Section: Discussionmentioning

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.

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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: Discussionmentioning

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.

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111

112

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“…The liver is a major site of cytochrome P450-mediated in vivo EET formation (30,42) and, as indicated by their regio-and stereochemical properties (37,42), the likely source of the EETs present in circulating plasma lipoproteins (43). Analysis of EET levels in the liver and plasma of Wy 14643-treated rats suggests that, in addition to phospholipid esterification (21), enzymatic hydration (20), and ␤-oxidation (22), the hepatic /-1-hydroxylation of these bioactive lipids could play important functional roles by altering either their bioactivity profiles and/or potency or by participating in their catabolism and disposition. As shown in Table VI 5 , purified rat liver cytochrome P450 reductase, and 50 g/ml of dilauroylphosphatidylcholine.…”

Section: Fig 4 Effects Of Anti-cyp4a1 and Anti-cyp4a2 Antibodies Onmentioning

confidence: 99%

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

Cowart

Wei²,

Hsu

et al. 2002

Journal of Biological Chemistry

178

152

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Cytochromes P450 of the CYP2C and CYP4A gene subfamilies metabolize arachidonic acid to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) and to 19-and 20-hydroxyeicosatetraenoic acids (HETEs), respectively. Abundant functional studies indicate that EETs and HETEs display powerful and often opposing biological activities as mediators of ion channel activity and regulators of vascular tone and systemic blood pressures. Incubation of 8,9-, 11,12-, and 14,15-EETs with microsomal and purified forms of rat CYP4A isoforms led to rapid NADPH-dependent metabolism to the corresponding 19-and 20-hydroxylated EETs. Comparisons of reaction rates and catalytic efficiency with those of arachidonic and lauric acids showed that EETs are one of the best endogenous substrates so far described for rat CYP4A isoforms. CYP4A1 exhibited a preference for 8,9-EET, whereas CYP4A2, CYP4A3, and CYP4A8 preferred 11,12-EET. In general, the closer the oxido ring is to the carboxylic acid functionality, the higher the rate of EET metabolism and the lower the regiospecificity for the EET -carbon. Analysis of cis-parinaric acid displacement from the ligand-binding domain of the human peroxisome proliferator-activated receptor-␣ showed that -hydroxylated 14,15-EET bound to this receptor with high affinity (K i ‫؍‬ 3 ؎ 1 nM). Moreover, at 1 M, the -alcohol of 14,15-EET or a 1:4 mixture of the -alcohols of 8,9-and 11,12-EETs activated human and mouse peroxisome proliferator-activated receptor-␣ in transient transfection assays, suggesting a role for them as endogenous ligands for these orphan nuclear receptors.Cytochromes P450 of the CYP4A gene subfamily are structurally and functionally conserved fatty-acid hydroxylases that are expressed in most mammalian tissues, including rat and human kidney and liver (1-7). These enzymes are selective for the /-1-hydroxylation of saturated and unsaturated fatty acids (1-7) and lack known roles in drug metabolism. The expression of some CYP4A isoforms is under the control of the peroxisome proliferator-activated receptor-␣ (PPAR␣) 1 (8 -13) and regulated by a variety of physiological and pathophysiological stimuli, including dietary fatty acids, hormones, diabetes, and starvation (9 -13). Interest in the molecular and functional properties of these enzymes has been stimulated by the demonstration of their role in the /-1-hydroxylation of arachidonic acid (AA) (4 -7) and the powerful biological activities of 19-and 20-hydroxyeicosatetraenoic acids (HETEs) as modulators of renal ion fluxes and vasoactivity (14 -18). Based on biochemical and functional correlates of CYP4A renal expression, 20-HETE biosynthesis, and the onset of systemic high blood pressure in the SHR/WKY rat model of spontaneous hypertension, a pro-hypertensive role for 20-HETE and CYP4A isoforms was proposed (14).The cytochrome P450 AA epoxygenase catalyzes the in vivo regio-and enantioselective metabolism of AA to epoxyeicosatrienoic acids (EETs) (16). Studies with microsomal and/or purified cytochrome P450 preparations showed tha...

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“…20-HETE also is converted to a bronchodilator substance by the pulmonary endothelial cyclooxygenase (24). In an attempt to better understand the mechanism of these endothelium-dependent effects, we have investigated the utilization of 20-HETE in porcine coronary artery endothelial cells (PCEC), an experimental model that we have used previously for biochemical studies of eicosanoid metabolism (25)(26)(27)(28). To investigate the potential functional significance of these observations, we examined the vasoactivity of 20-HETE and 20-carboxy-arachidonic acid (20-COOH-AA), its main metabolite (19), in an isolated porcine coronary microvessel preparation.…”

Section: -Hydroxyeicosatetraenoic Acid (Hete)mentioning

confidence: 99%

“…After removal of the solvent under N 2 , the lipid extract was dissolved in acetonitrile and further separated by reverse phase HPLC with a solvent system consisting of H 2 O adjusted to pH 4.0 with formic acid and an acetonitrile gradient that increased from 30 to 100% over 70 min (29). The product was collected, dried under N 2 , and analyzed by liquid chromatography combined with mass spectrometry (27). The mass spectrum was obtained by using an Agilent 1100 MSD liquid chromatography-mass spectrometry system with source collision-induced decomposition (27).…”

Section: Synthesis Of 20-[ 3 H]hete-20-[mentioning

confidence: 99%

20-Hydroxyeicosatetraenoic Acid (20-HETE) Metabolism in Coronary Endothelial Cells

Kaduce

Fang

Harmon

et al. 2004

Journal of Biological Chemistry

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Pathways of Epoxyeicosatrienoic Acid Metabolism in Endothelial Cells

Cited by 177 publications

References 42 publications

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

Inhibitors of soluble epoxide hydrolase attenuate vascular smooth muscle cell proliferation

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

20-Hydroxyeicosatetraenoic Acid (20-HETE) Metabolism in Coronary Endothelial Cells

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