Identification of 13-Hydroxy-14,15-epoxyeicosatrienoic Acid as an Acid-stable Endothelium-derived Hyperpolarizing Factor in Rabbit Arteries

Chawengsub, Yuttana; Gauthier, Kathryn M.; Nithipatikom, Kasem; Hammock, Bruce D.; Falck, John R.; Dubasi, Narsimhaswamy; Campbell, William B.

doi:10.1074/jbc.m109.025627

Cited by 19 publications

(19 citation statements)

References 57 publications

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“…Any elaboration on the identity of the latter is necessarily speculative, although direct activation of a hitherto unknown DA dilator is a possibility. In this connection, it is relevant to recall the recent identification in other blood vessels of novel, CYP450-based, dilator eicosanoids [26,27] as well as the increasing importance being assigned to hydrogen sulfide in the regulation of vascular tone [28] . Conversely, vasodilatation could result from interference with some factor, such as the Rho/Rho kinase complex, that is critical for the contractile tension of blood vessels, DA included [12,29] .…”

Section: Discussionmentioning

confidence: 99%

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

et al. 2011

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Background: Microsomal prostaglandin E synthase-1 (mPGES1) is critical for prostaglandin E₂ formation in ductus arteriosus (DA) and, accordingly, in its patency. We previously reported that mPGES1 deletion, unlike cyclo-oxygenase (COX) suppression, is not followed by upregulation of relaxant nitric oxide (NO). Consequently, we proposed that a mPGES1 inhibitor may be better than currently used COX inhibitors in managing premature infants with persistent DA (PDA). Objective: To assess the effect of the mPGES1 inhibitor, 2-(6-chloro-1H-phenanthro[9,10d]imidazole-2-yl)isophthalonitrile (MF63) on DA ex vivo and in vivo (p.o. to the mother). Methods: Experiments were carried out with mice bearing human mPGES1. We utilized isolated, wire-mounted DA for isometric recording and a whole-body freezing technique to assess the DA caliber as it occurs in vivo. Results: MF63 (10 µM) contracted the isolated DA. DA constriction was also seen in vivo after a single 10-mg kg^–1 dose. Conversely, a 30-mg kg^–1 dose gave inconsistent results, combining constriction with no effect. DA dilatation followed instead a repeated lower dose (twice daily for 3 days), and postnatal closure of the vessel was also delayed. Chronic pretreatment had no effect on endothelial NO synthase mRNA expression in fetal DA, nor did it modify the contraction to NO synthase inhibitor N^G-nitro-L-arginine methyl ester (100 µM). Conclusions: MF63 has a dual action on DA, the constriction being associated with accessory dilatation. The latter effect should be explained before considering further a mPGES1 inhibitor for management of PDA.

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Section: Discussionmentioning

confidence: 99%

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

et al. 2011

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“…A secondary oxidation requiring cysteine and iron yields the EKODE product 12,13-epoxy-9-oxo-10- trans -octadecenoic acid (44, 45). AA can also be metabolized to similar products, 11, 12, 15-hydroxyeicosatrienoic acid (THETA) and its unstable precursor 15-hydroxy-11,12-epoxyeicosatrienoic acid (HEETA), through a combination of CYP2J2 and 15-LO (47). In addition, a more stable HEETA stereoisomer is produced by oxygenation at C13–15, giving cis and trans products of 13-hydroxy-14,15-epoxyeicosatrienoic acid.…”

Section: Epoxidesmentioning

confidence: 99%

Redox-Dependent Anti-Inflammatory Signaling Actions of Unsaturated Fatty Acids

Delmastro-Greenwood

Freeman

Wendell

2014

Annu. Rev. Physiol.

104

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Unsaturated fatty acids are metabolized to reactive products that can act as pro- or anti-inflammatory signaling mediators. Electrophilic fatty acid species, including nitro- and oxo-containing fatty acids, display salutary anti-inflammatory and metabolic actions. Electrophilicity can be conferred by both enzymatic and oxidative reactions, via the homolytic addition of nitrogen dioxide to a double bond or via the formation of α,β-unsaturated carbonyl and epoxide substituents. The endogenous formation of electrophilic fatty acids is significant and influenced by diet, metabolic, and inflammatory reactions. Transcriptional regulatory proteins and enzymes can sense the redox status of the surrounding environment upon electrophilic fatty acid adduction of functionally significant, nucleophilic cysteines. Through this covalent and often reversible posttranslational modification, gene expression and metabolic responses are induced. At low concentrations, the pleiotropic signaling actions that are regulated by these protein targets suggest that some classes of electrophilic lipids may be useful for treating metabolic and inflammatory diseases.

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“…Several data, for example, implicate this pathway in synaptic function (DeCostanzo et al 2010). In addition, the initial metabolite (i.e., hydroperoxy product) in this and the allied 15-lipoxygenase pathways yields diverse active products (Pace-Asciak et al 1999;Chawengsub et al 2009). Significantly, this transformation may require the presence of a CYP450 hemoprotein, operating though as a hydroperoxide isomerase rather than an epoxygenase (Chawengsub et al 2009).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the initial metabolite (i.e., hydroperoxy product) in this and the allied 15-lipoxygenase pathways yields diverse active products (Pace-Asciak et al 1999;Chawengsub et al 2009). Significantly, this transformation may require the presence of a CYP450 hemoprotein, operating though as a hydroperoxide isomerase rather than an epoxygenase (Chawengsub et al 2009). Hence, given the great potential of the eicosanoid system, it is not too far-fetched to think that the putative oxygen messenger may derive from the concerted operation of 2 distinct AA pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Knowing the importance of the eicosanoid system in the control of blood vessels, the ductus included (Smith 1998), we have attempted in the past to link the oxygen contraction of the ductus to an arachidonic acid (AA) epoxide (i.e., epoxyeicosatrienoic acid (EET)) but results have been negative (Coceani et al 1988). Lately, however, this system has acquired a greater degree of complexity with the characterization of a host of vasoactive agents, originating through epoxygenaseand lipoxygenase-based reactions (Pace-Asciak et al 1999;Chen et al 2008;Chawengsub et al 2009), and the realization of the potential for synthesis still being unfulfilled. Furthermore, a product of AA u-hydroxylation, 20-hydroxyeicosatetraenoic acid (20-HETE), has been implicated in oxygen sensing of the systemic microvasculature (Kunert et al 2001).…”

Section: Introductionmentioning

confidence: 99%

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Arachidonic acid epoxygenase and 12(S)-lipoxygenase: evidence of their concerted involvement in ductus arteriosus constriction to oxygen

Baragatti

Coceani

2011

Can. J. Physiol. Pharmacol.

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Oxygen promotes closure of the ductus arteriosus at birth. We have previously presented a scheme for oxygen action with a cytochrome P450 (CYP450) hemoprotein and endothelin-1 (ET-1) being, respectively, sensor and effector, and a hypothetical monooxygenase product serving as a coupling link. We have also found in the vessel arachidonic acid (AA) 12(S)-lipoxygenase (12-lipoxygenase) undergoing upregulation at birth. Here, we examined the feasibility of a sensor-to-effector messenger originating from AA monooxygenase and 12-lipoxygenase pathways. The epoxygenase inhibitor, N-methylsulfonyl-6-(2-)hexanamide, suppressed the tonic contraction of ductus to oxygen. A similar effect was obtained with 12-lipoxygenase inhibitors baicalein and PD 146176. By contrast, none of the inhibitors modified the endothelin-1 contraction. Furthermore, an AA ω-hydroxylation product, 20-hydroxyeicosatetraenoic acid (20-HETE), reportedly responsible for oxygen contraction in the systemic microvasculature, had no such effect on the ductus. We conclude that AA epoxygenase and 12-lipoxygenase jointly produce a hitherto uncharacterized compound acting as oxygen messenger in the ductus.

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Identification of 13-Hydroxy-14,15-epoxyeicosatrienoic Acid as an Acid-stable Endothelium-derived Hyperpolarizing Factor in Rabbit Arteries

Cited by 19 publications

References 57 publications

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

Dual, Constrictor-to-Dilator, Response of the Mouse Ductus Arteriosus to the Microsomal Prostaglandin E Synthase-1 Inhibitor, 2-(6-Chloro-1H-phenanthro[9,10<i>d</i>]imidazole- 2-yl)isophthalonitrile

Redox-Dependent Anti-Inflammatory Signaling Actions of Unsaturated Fatty Acids

Arachidonic acid epoxygenase and 12(S)-lipoxygenase: evidence of their concerted involvement in ductus arteriosus constriction to oxygen

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