Cyclooxygenase (COX)-1 and COX-2 Participate in 5,6-Epoxyeicosatrienoic Acid-Induced Contraction of Rabbit Intralobar Pulmonary Arteries

Moreland, Kirby T.; Procknow, Jesse D.; Sprague, Randy S.; Iverson, Jennifer L.; Lonigro, Andrew J.; Stephenson, Alan H.

doi:10.1124/jpet.106.107904

Cited by 24 publications

(13 citation statements)

References 38 publications

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“…The minor expression of COX-1 in the AA corroborates with previous work in rabbit vessels, such as femoral (28), intralobar pulmonary (20), carotid (17), and small mesenteric (32) arteries. The present study extends those previous studies by showing a similar COX-1 expression in the aorta of normal and atherosclerotic AA, which was mainly localized in the adventitia.…”

Section: Discussionsupporting

confidence: 78%

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

Foudi

Norel²,

Rienzo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions.

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Section: Discussionsupporting

confidence: 78%

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

Foudi

Norel²,

Rienzo³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…S1, 5,6-, 8,9-, and to a lesser extent 11,12-EET were substrates in the presence of both enzymes, yielding measurable oxygen consumption over 25 s at 50 μM. 5,6-EET, reported to be a COX substrate (18,19), noticeably reacted with COX-1 and COX-2 at concentrations ranging between 15 and 50 μM (SI Appendix, Fig. S2).…”

Section: Resultsmentioning

confidence: 99%

“…Although EETs are primarily metabolized by sEH, a few studies have observed that the 5,6-EET and 8,9-EET are substrates for COX-1 (17,18) and COX-2 (19). The COX metabolites of EETs have largely undefined biological activity, yet Homma et al determined that the ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) metabolite is a renal vasoconstrictor and potent mitogen, approximately three orders of magnitude more potent than its parent, 8,.…”

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confidence: 99%

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Rand

Barnych

Morisseau

et al. 2017

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

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Arachidonic acid (ARA) is metabolized by cyclooxygenase (COX) and cytochrome P450 to produce proangiogenic metabolites. Specifically, epoxyeicosatrienoic acids (EETs) produced from the P450 pathway are angiogenic, inducing cancer tumor growth. A previous study showed that inhibiting soluble epoxide hydrolase (sEH) increased EET concentration and mildly promoted tumor growth. However, inhibiting both sEH and COX led to a dramatic decrease in tumor growth, suggesting that the contribution of EETs to angiogenesis and subsequent tumor growth may be attributed to downstream metabolites formed by COX. This study explores the fate of EETs with COX, the angiogenic activity of the primary metabolites formed, and their subsequent hydrolysis by sEH and microsomal EH. Three EET regioisomers were found to be substrates for COX, based on oxygen consumption and product formation. EET substrate preference for both COX-1 and COX-2 were estimated as 8,9-EET > 5,6-EET > 11,12-EET, whereas 14,15-EET was inactive. The structure of two major products formed from 8,9-EET in this COX pathway were confirmed by chemical synthesis: ct-8,9-epoxy-11-hydroxy-eicosatrienoic acid (ct-8,9-E-11-HET) and ct-8,9-epoxy-15-hydroxy-eicosatrienoic acid (ct-8,9-E-15-HET). ct-8,9-E-11-HET and ct-8,9-E-15-HET are further metabolized by sEH, with ct-8,9-E-11-HET being hydrolyzed much more slowly. Using an s.c. Matrigel assay, we showed that ct-8,9-E-11-HET is proangiogenic, whereas ct-8,9-E-15-HET is not active. This study identifies a functional link between EETs and COX and identifies ct-8,9-E-11-HET as an angiogenic lipid, suggesting a physiological role for COX metabolites of EETs.omega-6 fatty acids | epoxyeicosatrienoic acids | metabolism | cyclooxygenase | angiogenesis A rachidonic acid (ARA) is an omega-6 fatty acid that is metabolized by three major classes of enzymes, cyclooxygenases (COXs), lipoxygenases, and cytochrome P450s (CYPs), to produce an array of biologically active metabolites (1-3). The CYP pathway transforms ARA into four epoxyeicosatrienoic acids (EETs) in addition to hydroxylated metabolites (1). EETs have several biological actions, and are considered antihypertensive, antiinflammatory, neuroprotective, cardioprotective, and analgesic (4). EETs also play a role in angiogenesis (5-10), the formation of new blood vessels from preexisting vessels that is important for many physiological and pathological processes, including cancer (11).EETs can enhance tumor growth and metastasis through their angiogenic activity (12); however, this activity is transient due to their metabolic instability. EETs are further metabolized by epoxide hydrolases (EHs), primarily soluble epoxide hydrolase (sEH), to their corresponding diols (4, 13), which are generally not biologically active (14) (Fig. 1A). Inhibition of sEH prolongs EET biological activity, potentiating their angiogenic activity, leading to increased tumor growth and metastasis in some systems (12, 15) (Fig. 1B).ARA can also be metabolized by COX to form proangiogenic and proinflammator...

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“…All of the above-described phenotypic alterations may well be the result of alterations in the production, catabolism and/or function of eicosanoids: bioactive mediators derived from arachidonic acid via -6 fatty acids (including prostaglandins, prostacyclins, leukotrienes, thromboxanes, hepoxilins, and lipoxins) and bioactive mediators derived from eicosapentaenoic acid and docosahexaenoic acid via -3 fatty acids, (including resolvins, docosatrienes, eoxins, and neuroprotectins). Eicosanoids exert largely unappreciated complex control over virtually all physiological processes: inflammation (Chiang et al, 2005;Leone et al, 2007;Mariotto et al, 2007;Serhan, 2007;Seubert et al, 2007), resolution phase of inflammation (Serhan, 2007), innate immunity (Ballinger et al, 2007), cardiopulmonary and vascular functions (Moreland et al, 2007;Seubert et al, 2007), angiogenesis (Fleming, 2007;Inceoglu et al, 2007), sensor of vascular pO 2 (Sacerdoti et al, 2003), bowel motility (Proctor et al, 1987), regulation of lipid metabolism and insulin sensitivity (Larsen et al, 2007;Nigam et al, 2007;Spector and Norris, 2007), central nervous system functions (Miyata and Roman, 2005;Jakovcevic and Harder, 2007), modulation of non-neuropathic pain (Inceoglu et al, 2007), neurohormone secretion and release (Inceoglu et al, 2007), fibrinolysis (Westlund et al, 1991;Jiang, 2007), inhibition of platelet aggregation (Westlund et al, 1991;Jiang, 2007), reproductive success (Cha et al, 2006;Weems et al, 2006), blastocyst implantation (Cha et al, 2006;Kennedy et al, 2007), early embryonic as well as fetal development (Cha et al, 2006), stimulation of tyrosine phosphorylation (Chen et al, 1998), G protein-si...…”

Section: Discussionmentioning

confidence: 99%

Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

et al. 2008

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Crossing the Cyp1a1/1a2(Ϫ/Ϫ) double-knockout mouse with the Cyp1b1(Ϫ/Ϫ) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(Ϫ/Ϫ) triple-knockout mouse. In this tripleknockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(Ϫ/Ϫ) produced the same degree of marked immunosuppression as seen in the Cyp1a1(Ϫ/Ϫ) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(Ϫ/Ϫ) mice showed the same "rescued" response as that seen in the Cyp1a1/1b1(Ϫ/Ϫ) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up-and 62 genes down-regulated (P-value <0.00086). Gene Ontology "classes of genes" most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect downregulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and activities.

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Cyclooxygenase (COX)-1 and COX-2 Participate in 5,6-Epoxyeicosatrienoic Acid-Induced Contraction of Rabbit Intralobar Pulmonary Arteries

Cited by 24 publications

References 38 publications

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits

Cyclooxygenase-derived proangiogenic metabolites of epoxyeicosatrienoic acids

Phenotype of theCyp1a1/1a2/1b1(-/-) Triple-Knockout Mouse

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