The vasodilator 17,18‐epoxyeicosatetraenoic acid targets the pore‐forming BK α channel subunit in rodents

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191

168

This article is available online at http://www.jlr.org Cytochrome P450 (CYP) enzymes catalyze the formation of biologically active epoxy-and hydroxy-metabolites of long-chain PUFAs ( 1 ). Traditionally, and in line with the prevalence of n-6 PUFAs in the "Western diet", arachidonic acid (AA) (20:4 n-6) has been considered as the main precursor and the corresponding metabolites were categorized as a subclass of eicosanoids ( 2 ). CYP-eicosanoid formation is also known as the "third branch of the AA cascade," complementary to the previously discovered cyclooxygenase (COX)-and lipoxygenase (LOX)-initiated pathways of prostanoid and leukotriene formation ( 3, 4 ).Physiologically important AA-derived CYP-eicosanoids include a set of regio-and stereoisomeric epoxyeicosatrienoic acids (EETs) and 20-HETE ( 2, 5 ). EETs and 20-HETE play partially opposing roles in the regulation of vascular, renal, and cardiac function ( 6-9 ). The contribution of EETs to cardiovascular function is infl uenced by the soluble epoxide hydrolase (sEH) that metabolizes EETs to less potent dihydroxyeicosatrienoic acids (DHETs) ( 10 ). Imbalances in CYP-eicosanoid formation are linked to the development of endothelial dysfunction and hypertension; ischemia-induced injury of the heart, kidney and brain; infl ammatory disorders; and atherosclerosis (11)(12)(13)(14)(15)(16)(17).Recent studies demonstrated that the same CYP isoforms that epoxidize or hydroxylate AA, also effi ciently metabolize

Section: Discussionmentioning

confidence: 99%

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

Fischer

Konkel

Mehling³

et al. 2014

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“…CYP epoxygenases also convert the 3-PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to epoxy-derivatives ( 9 ), which are potent dilators of coronary arterioles ( 10-12 ) or pulmonary artery ( 13 ) and inhibit platelet aggregation ( 14 ). The EPA-derived epoxides account for fi ve epoxyeicosatetraenoic acids (5,8,11,14,and 17,, whereas the DHA-derived epoxides account for six epoxydocosapentaenoic acids (4,7,10,13,16,and 19,. A high regio-and stereoselectivity has been observed when testing the effects of chemically synthesized epoxides from AA and EPA.…”

mentioning

confidence: 90%

Stereoselective epoxidation of the last double bond of polyunsaturated fatty acids by human cytochromes P450

Lucas

Goulitquer

Marienhagen

et al. 2010

family 1 to 3 are mainly epoxygenases, whereas CYP isoforms from family 4 are mainly -hydroxylases ( 4, 5 ).CYP epoxygenases convert arachidonic acid (AA) to four epoxyeicosatrienoic acid regioisomers (5,8,11,and 14, that function as lipid mediators. EETs produce vascular relaxation, have antiinfl ammatory effects on blood vessels and in the kidney, promote angiogenesis, and protect ischemic myocardium and brain [for review, see ( 6-8 )]. CYP epoxygenases also convert the 3-PUFA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to epoxy-derivatives ( 9 ), which are potent dilators of coronary arterioles ( 10-12 ) or pulmonary artery ( 13 ) and inhibit platelet aggregation ( 14 ). The EPA-derived epoxides account for fi ve epoxyeicosatetraenoic acids (5,8,11,14,and 17,, whereas the DHA-derived epoxides account for six epoxydocosapentaenoic acids (4,7,10,13,16,and 19,. A high regio-and stereoselectivity has been observed when testing the effects of chemically synthesized epoxides from AA and EPA. For example, in the rat, renal arteries were dilated by 11(R),12(S)-EET but not by 11(S),12(R)-EET or 14,15-EET enantiomers ( 15 ). Also in rats, among all EETeTr enantiomers, only the 17(R),18(S)-enantiomer, not 17(S),18(R), was effective on calcium-activated potassium (BK) channels in isolated cerebral arteries ( 11 ). However, in porcine coronary microvessels, all regioisomeric EETeTrs had similar Cytochromes P450 (CYPs) belong to a protein superfamily among which some members metabolize polyunsaturated long-chain fatty acids (PUFA-LC) to several classes of oxygenated metabolites. The product profi les depend on the involved CYP isoforms and may consist of a series of regio-and stereo-isomeric epoxides and hydroxylated compounds ( 1-3 ). In humans, CYP isoforms from

“…The mechanism involves activation of BK Ca channels, with the 17,18-EETr targeting the pore-forming BK a subunit (49). This suggests that some beneficial effects of omega-3 fatty acid supplementation may be due to conversion of eicosapentaenoic acid to 17,18-EETr.…”

Section: Omega-3 Eet Analogsmentioning

confidence: 99%

Arachidonic acid cytochrome P450 epoxygenase pathway

Spector

2009

350

311

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...