Hepoxilin signaling in intact human neutrophils: biphasic elevation of intracellular calcium by unesterified hepoxilin A<sub>3</sub>

Reynaud, Dénis; Demin, Peter; Sutherland, Mark; Nigam, Santosh; Pace-Asciak, Cecil R.

doi:10.1016/s0014-5793(99)00225-2

Cited by 24 publications

(20 citation statements)

References 9 publications

(11 reference statements)

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“…In the brain, hepoxilins modulate synaptic neurotransmission and neuronal excitability, mostly through stimulation of intracellular calcium release or increased calcium infl ux into the cell (34)(35)(36)(37). Hepoxilins are considered pro-infl ammatory because increased hepoxilin and trioxilin levels have been found in psoriatic lesions ( 38 ) and HxA 3 was shown to regulate neutrophil migration in response to infl ammation ( 39,40 ).…”

Section: Enzyme Assaysmentioning

confidence: 99%

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Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Cronin

Decker

Arand

2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org of an epoxide hydrolase (EH) and a lipid phosphatase in each of its subunits ( 2-4 ). The sEH is abundantly expressed throughout the organism ( 5, 6 ) and accepts a broad range of substrates ( 7,8 ), in particular, endogenous epoxides derived from unsaturated fatty acids such as epoxyeicosatrienoic acids (EETs) ( 9 ). The organism utilizes these lipid epoxides as important signaling molecules, which regulate a variety of physiological functions. EETs were identifi ed as endothelium-derived hyperpolarizing factors (EDHFs) ( 10 ) acting on vascular smooth muscle cells leading to hyperpolarization and vasodilation ( 11,12 ). Since then, several experimental hypertensive models confi rmed a role for EETs in blood pressure regulation and end organ protection ( 13,14 ). Further, EETs have anti-infl ammatory and antinociceptive properties ( 15-17 ) and fi nally, seem to promote cell proliferation, migration, and angiogenesis (18)(19)(20).The metabolism of these lipid epoxides by sEH to the corresponding diols is generally considered a deactivation process. For this reason, the sEH is a promising target for the treatment of hypertension, infl ammatory diseases, pain, diabetes, and stroke ( 16,(21)(22)(23)(24)(25). A number of sEH inhibitors (sEHIs) have been developed ( 26, 27 ) for therapeutic applications. Yet the sEH also serves some function in xenobiotic metabolism by accepting certain trans -substituted epoxides, which are very poor substrates for microsomal epoxide hydrolase (mEH) ( 28,29 ).Other epoxide hydrolases with rather narrow substrate selectivity have been identifi ed in mammals. Of those, hepoxilin A 3 epoxide hydrolase (hepoxilin hydrolase, EC Abstract Hepoxilins are lipid signaling molecules derived from arachidonic acid through the 12-lipoxygenase pathway. These trans -epoxy hydroxy eicosanoids play a role in a variety of physiological processes, including infl ammation, neurotransmission, and formation of skin barrier function. Mammalian hepoxilin hydrolase, partly purifi ed from rat liver, has earlier been reported to degrade hepoxilins to trioxilins. Here, we report that hepoxilin hydrolysis in liver is mainly catalyzed by soluble epoxide hydrolase (sEH): i ) purifi ed mammalian sEH hydrolyses hepoxilin A 3 and B 3 with a V max of 0.4-2.5 mol/mg/min; ii ) the highly selective sEH inhibitors N-adamantyl-N'-cyclohexyl urea and 12-(3-adamantan-1-yl-ureido) dodecanoic acid greatly reduced hepoxilin hydrolysis in mouse liver preparations; iii ) hepoxilin hydrolase activity was abolished in liver preparations from sEH ؊ / ؊ mice; and iv ) liver homogenates of sEH ؊ / ؊ mice show elevated basal levels of hepoxilins but lowered levels of trioxilins compared with wild-type animals . We conclude that sEH is identical to previously reported hepoxilin hydrolase. This is of particular physiological relevance because sEH is emerging as a novel drug target due to its major role in the hydrolysis of important lipid signaling molecules such as epoxyeicosatrien...

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Section: Enzyme Assaysmentioning

confidence: 99%

“…A hepoxilin receptor has not been identifi ed, but several reports ( 34,(47)(48)(49) support its existence.…”

mentioning

confidence: 99%

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Cronin

Decker

Arand

2011

Journal of Lipid Research

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“…Stimulation of PMN migration by hepA 3 appears to occur via Ca 2ϩ signaling induced by activation of an intracellular receptor (15), which leads to reorganization of Ca 2ϩ within PMNs from the endoplasmic reticulum into mitochondria (16). HepA 3 binding to an unidentified receptor in human PMNs shows clear specificity (17) in a manner similar to findings obtained in our studies (Table 1), further supporting the overall identification of hepA 3 as a stimulator of PMN migration across the epithelial TJ without premature degranulation (5), previously known as PEEC.…”

Section: Examination Of Metabolic Pathwaysmentioning

confidence: 99%

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Mrsny

Gewirtz

Siccardi

et al. 2004

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

156

225

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The mechanism by which neutrophils [polymorphonuclear leukocyte (PMNs)] are stimulated to move across epithelial barriers at mucosal surfaces has been basically unknown in biology. IL-8 has been shown to stimulate PMNs to leave the bloodstream at a local site of mucosal inflammation, but the chemical gradient used by PMNs to move between adjacent epithelial cells and traverse the tight junction at the apical neck of these mucosal barriers has eluded identification. Our studies not only identify this factor, previously termed pathogen-elicited epithelial chemoattractant, as the eicosanoid hepoxilin A 3 (hepA3) but also demonstrate that it is a key factor promoting the final step in PMN recruitment to sites of mucosal inflammation. We show that hepA 3 is synthesized by epithelial cells and secreted from their apical surface in response to conditions that stimulate inflammatory events. Our data further establish that hepA 3 acts to draw PMNs, via the establishment of a gradient across the epithelial tight junction complex. The functional significance of hepA 3 to target PMNs to the lumen of the gut at sites of inflammation was demonstrated by the finding that disruption of the 12-lipoxygenase pathway (required for hepA 3 production) could dramatically reduce PMN-mediated tissue trauma, demonstrating that hepA 3 is a key regulator of mucosal inflammation. Bacterial pathogens continually confront epithelial barriers of the body, such as those of the gastrointestinal, respiratory, and reproductive tracts. Polymorphonuclear leukocyte (PMNs) represent a class of white cells critical to defend the host from such pathogens. Previous studies have identified factors such as IL-8, secreted from the basolateral surface of epithelial barriers that establish chemical gradients essential for PMN activation and recruitment from the bloodstream (1). After this IL-8 gradient, PMNs are drawn to the lateral surfaces of epithelial cells. Migration to the actual site of bacterial infection, however, i.e., within the intestinal lumen, requires the action(s) of an additional chemical gradient established across a final barrier present at the apical neck of epithelia, the tight junction (TJ) complex. Any molecule that could function to establish a gradient across such a barrier would have unique properties: selective secretion from the apical rather than basolateral epithelial cell surface, capacity to permeate the TJ to establish a chemical gradient, and a labile nature that would prevent excessive PMN migration. Identification of such a factor has been an important unanswered question of epithelial pathobiology.Salmonellosis, a frequent cause of diarrhea worldwide, represents one example of epithelial pathobiology where extensive PMN transmigration into the lumen is observed, in this case into small intestine crypts in response to apical infection by Salmonella typhimurium. PMN actions on the epithelium, culminating in the formation of intestinal crypt abscesses and subsequent loss of barrier function, underline the key events in mediat...

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“…The hepoxilin metabolites likely alter the intracellular concentrations of ions, including calcium and potassium ions, as well dictating alterations in second messenger systems [12]. Recent evidence suggests that the biological actions of the hepoxilins may be receptor-mediated as indicated from data showing the existence of hepoxilin-specific binding proteins in the human neutrophil [15]. Hepoxilin A 3 has also been implicated as an endogenous lipid mediator opposing hypotonic swelling of intact human platelets [16].…”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

Epoxide hydrolases: biochemistry and molecular biology

Fretland

Omiecinski

2000

Chemico-Biological Interactions

273

185

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Epoxides are organic three-membered oxygen compounds that arise from oxidative metabolism of endogenous, as well as xenobiotic compounds via chemical and enzymatic oxidation processes, including the cytochrome P450 monooxygenase system. The resultant epoxides are typically unstable in aqueous environments and chemically reactive. Biol. Chem. 260 (1985) 1630-1640). Therefore, it is of vital importance for the biological organism to regulate levels of these reactive species. The epoxide hydrolases (E.C. 3.3.2.3) belong to a sub-category of a broad group of hydrolytic enzymes that include esterases, proteases, dehalogenases, and lipases Beetham et al. (DNA Cell Biol. 14 (1995) 61 -71). In particular, the epoxide hydrolases are a class of proteins that catalyze the hydration of chemically reactive epoxides to their corresponding dihydrodiol products. Simple epoxides are hydrated to their corresponding vicinal dihydrodiols, and arene oxides to trans-dihydrodiols. In general, this hydration leads to more stable and less reactive intermediates, however exceptions do exist. In mammalian species, there are at least five epoxide hydrolase forms, microsomal cholesterol 5,6-oxide hydrolase, hepoxilin A 3 hydrolase, leukotriene A 4 hydrolase, soluble, and microsomal epoxide hydrolase. Each of these enzymes is distinct chemically and immunologically. Table 1 illustrates some general properties for each of these classes of hydrolases. Fig. 1 provides an overview of selected model substrates for each class of epoxide hydrolase.

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Hepoxilin signaling in intact human neutrophils: biphasic elevation of intracellular calcium by unesterified hepoxilin A₃

Cited by 24 publications

References 9 publications

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Epoxide hydrolases: biochemistry and molecular biology

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Hepoxilin signaling in intact human neutrophils: biphasic elevation of intracellular calcium by unesterified hepoxilin A3

Cited by 24 publications

References 9 publications

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase

Identification of hepoxilin A3in inflammatory events: A required role in neutrophil migration across intestinal epithelia

Epoxide hydrolases: biochemistry and molecular biology

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Hepoxilin signaling in intact human neutrophils: biphasic elevation of intracellular calcium by unesterified hepoxilin A₃

Identification of hepoxilin A₃in inflammatory events: A required role in neutrophil migration across intestinal epithelia