Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide

Fang, Xiang; Weintraub, Neal L.; Oltman, Christine L.; Stoll, Lynn L.; Kaduce, Terry L.; Harmon, Shawn D.; Dellsperger, Kevin C.; Morisseau, Christophe; Hammock, Bruce D.; Spector, Arthur A.

doi:10.1152/ajpheart.00448.2002

Cited by 43 publications

(68 citation statements)

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“…EETs undergo b-oxidation, forming 16-carbon epoxyderivatives that accumulate in the extracellular fluid, and they can be chain-elongated to form 22-carbon derivatives that are incorporated into phospholipids (15). As illustrated in Fig.…”

Section: Eet Synthesis Metabolism and Functionmentioning

confidence: 99%

Arachidonic acid cytochrome P450 epoxygenase pathway

Spector

2009

Journal of Lipid Research

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356

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Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four epoxyeicosatrienoic acid (EET) regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET, that function as autacrine and paracrine mediators. EETs produce vascular relaxation by activating smooth muscle large-conductance Ca 21 -activated K 1 channels (BK Ca ). In addition, they have anti-inflammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain. CYP epoxygenases also convert eicosapentaenoic acid to vasoactive epoxy-derivatives, and endocannabinoids containing 11,12-and 14,15-EET are formed. Many EET actions appear to be initiated by EET binding to a membrane receptor that activates ion channels and intracellular signal transduction pathways. However, EETs also are taken up by cells, are incorporated into phospholipids, and bind to cytosolic proteins and nuclear receptors, suggesting that some functions may occur through direct interaction of the EET with intracellular effector systems. Soluble epoxide hydrolase (sEH) converts EETs to dihydroxyeicosatrienoic acids (DHETs). Because this attenuates many of the functional effects of EETs, sEH inhibition is being evaluated as a mechanism for increasing and prolonging the beneficial actions of EETs. Epoxyeicosatrienoic acids (EET) are epoxide derivatives of arachidonic acid. They are formed by cytochrome P450 (CYP) epoxygenases and function as lipid mediators. Epoxidation can occur at any of the four double bonds of arachidonic acid, giving rise to four regioisomers, 5,6-, 8,9-, 11,12-, and 14,15-EET. EETs are synthesized in the endothelium and activate large-conductance Ca 21 -activated K 1 channels (BK Ca ), causing hyperpolarization of the vascular smooth muscle and vasorelaxation. Thus, EETs function as an endothelium-derived hyperpolarizing factor (EDHF) in a number of vascular beds, including the coronary and renal circulations, producing a decrease in blood pressure. Soluble epoxide hydrolase (sEH), which converts EETs to dihydroxyeicosatrienoic acids (DHETs), attenuates many of the functional effects of EETs. These seminal findings have been described in a number of detailed reviews (1-4). Recent results with cultured cells and animal models indicate that EETs have additional potentially beneficial effects on the vascular system, heart, kidneys, and nervous system, and many current studies are directed at these actions (5-9). The other current emphasis is on sEH inhibition as a therapeutic strategy for increasing the beneficial effects of EETs (10, 11). EET SYNTHESIS, METABOLISM, AND FUNCTIONEETs are synthesized by cells that express CYP epoxygenase activity. As illustrated in Fig. 1, these enzymes act on arachidonic acid released from phospholipids when cytosolic phospholipase A 2 (cPLA 2 ) is activated (12). The epoxygenase inserts an oxygen atom on a carbon attached to one of the double bonds of arachidonic acid, and the double bond is reduced as the epoxide forms. Each CYP epoxygenase produces several regioisomers, with one for...

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Section: Eet Synthesis Metabolism and Functionmentioning

confidence: 99%

Arachidonic acid cytochrome P450 epoxygenase pathway

Spector

2009

Journal of Lipid Research

Self Cite

356

311

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“…15 EETs are not all metabolized via the same pathway, and although 5,6-EET is a preferred substrate for cyclooxygenase, 16 8,9-, 11,12-and 14,15-EET are metabolized to the corresponding dihydroxy derivatives (the dihydroxyeicosatrienoic acids) by the soluble epoxide hydrolase (sEH), 17 as well as by ␤-oxidation. 18 This difference accounts for the finding that relaxation of the bovine coronary artery induced by a novel stable agonist of 5,6-EET, 5-(pentadeca-3(Z),6(Z),9(Z)-trienyloxy) pentanoic acid was inhibited by the cyclooxygenase inhibitor indomethacin. 19 The recent development of sEH inhibitors has helped to determine the physiological consequences of enhanced CYP activity and EET formation.…”

Section: Eets and Endothelium-derived Hyperpolarizing Factormentioning

confidence: 99%

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

2006

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Abstract-Epoxyeicosatrienoic acids (EETs) are epoxides of arachidonic acid generated by cytochrome P450 (CYP) epoxygenases. The activation of CYP epoxygenases in endothelial cells is an important step in the NO and prostacyclin-independent vasodilatation of several vascular beds, and EETs have been identified as an endotheliumderived hyperpolarizing factor. However, EETs also exert membrane potential-independent effects and modulate several signaling cascades that affect endothelial cell proliferation and angiogenesis. This review summarizes the role of CYP-derived EETs in endothelium-derived hyperpolarizing factor-mediated responses and highlights the evidence indicating that EETs are important second messengers involved in endothelial cell signaling pathways related to angiogenesis. (Hypertension. 2006;47:629-633.)Key Words: calcium channels Ⅲ endothelium-derived factors Ⅲ hypertension Ⅲ vasodilatation T here is now considerable evidence linking the metabolism of arachidonic acid by cytochrome P450 (CYP) enzymes with the regulation of vascular homeostasis and tone, as well as renal function. The enzymes in question fall into 2 classes: (1) the epoxygenases, which generate epoxyeicosatrienoic acids (EETs); and (2) the /-1 hydroxylases, which generate 20-hydroxyeicosatetraenoic acid (20-HETE). EETs and Endothelium-Derived Hyperpolarizing FactorInterest in the vascular actions of EETs was initially related to their identification as an endothelium-derived hyperpolarizing factor (EDHF), that is, compounds responsible for the NO and prostacyclin-independent but endothelium-dependent vasodilatation of some vascular beds. There is now convincing evidence indicating that the hyperpolarizing factor produced by coronary and renal arteries from several species (humans, pigs, cows, dogs, rats, and rabbits) displays characteristics similar to those of a cytochrome CYP-derived metabolite of arachidonic acid. 1 A CYP-dependent, EDHF response has also been described in other human arteries/vascular beds including the mammary artery, 2 the forearm vasculature, 3 and thigh skeletal muscle circulation. 4 However, the EDHFmediated relaxations in human mesenteric arteries 5 and renal arteries 6 appear to be independent of CYP activity. For those following the "EDHF story," the literature has been highly confusing, and for several years the field seemed caught in a pantomime of "it is" versus "it isn't" reports. One reason for the confusion was that although some EDHFmediated responses could be attributed to a CYP-derived metabolite of arachidonic acid, there were clearly other responses that occurred entirely independently of the activation of a CYP enzyme. For comprehensive reviews on the nature of the different EDHFs, the reader should consult references. [7][8][9] Part of the reason for some of the controversy was that EETs were initially reported to initiate smooth muscle hyperpolarization by activating iberiotoxin-sensitive large conductance Ca 2ϩ -activated K ϩ (BK Ca ) channels, 10 whereas EDHFdependent relaxation was mor...

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“…In the absence of the electron donor, the vicinal diols were mainly generated by human microsomes. Inhibition of EH-like from insect and liver microsomes with 100-200 M cyclohexane oxide and elaidamide was unsuccessful, although these compounds inhibited the EH from rat (43). A high level of vicinal diol formation was measured in liver for Z 14(15)-EET and Z 8(9)-EET.…”

Section: Eet and Aa Metabolismmentioning

confidence: 99%

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

Quéré

Plée-Gautier

Potin

et al. 2004

Journal of Lipid Research

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CYP4F isoforms are involved in the oxidation of important cellular mediators such as leukotriene B 4 (LTB4) and prostaglandins. The proinflammatory agent LTB4 and cytotoxic leukotoxins have been associated with several inflammatory diseases. We present evidence that the hydroxylation of Z 9(10)-epoxyoctadecanoic, Z 9(10)-epoxyoctadec-Z 12-enoic, and Z 12(13)-epoxyoctadec-Z 9-enoic acids and that of monoepoxides from arachidonic acid [epoxyeicosatrienoic acid (EET)] is important in the regulation of leukotoxin and EET activity. These three epoxidized derivatives from the C18 family (C18-epoxides) were converted to 18-hydroxy-C18-epoxides by human hepatic microsomes with apparent K m values of between 27.6 and 175 M. Among recombinant P450 enzymes, CYP4F2 and CYP4F3B catalyzed mainly the -hydroxylation of C18-epoxides with an apparent V max of between 0.84 and 15.0 min ؊ 1 , whereas the apparent V max displayed by CYP4F3A, the isoform found in leukocytes, ranged from 3.0 to 21.2 min ؊ 1 . The rate of -hydroxylation by CYP4A11 was experimentally found to be between 0.3 and 2.7 min ؊ 1 . CYP4F2 and CYP4F3 exhibited preferences for -hydroxylation of Z 8(9)-EET, whereas human liver microsomes preferred Z 11(12)-EET and, to a lesser extent, Z 8(9)-EET. Moreover, vicinal diol from both C18-epoxides and EETs were -hydroxylated by liver microsomes and by CYP4F2 and CYP4F3. These data support the hypothesis that the human CYP4F subfamily is involved in the -hydroxylation of fatty acid epoxides. These findings demonstrate that another pathway besides conversion to vicinal diol or chain shortening by ␤ -oxidation exists for fatty acid epoxide inactivation. -Le Quéré, V., E. Plée-Gautier, P. Potin, S. Madec, and J-P. Salaün. Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides.

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Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide

Cited by 43 publications

References 40 publications

Arachidonic acid cytochrome P450 epoxygenase pathway

Arachidonic acid cytochrome P450 epoxygenase pathway

Endothelium-Derived Epoxyeicosatrienoic Acids and Vascular Function

Human CYP4F3s are the main catalysts in the oxidation of fatty acid epoxides

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