| Cytochrome P450 subfamily 2J polypeptide 2 expression and circulating epoxyeicosatrienoic metabolites in preeclampsia. | |
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MedLine Citation:
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PMID: 23155181 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis, which are mechanistically important in preeclampsia. METHODS AND RESULTS: We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 control subjects. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. Reverse-transcription polymerase chain reaction confirmed the upregulation, and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 5,6-epoxyeicosatrienoic acid (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids, were elevated in preeclamptic women compared with controls in the latter two thirds of pregnancy and after delivery. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine tumor necrosis factor-α enhanced CYP2J2 gene and protein expression. In 2 independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic angiotensin II rat, we observed elevated EET, dihydroxyeicosatrienoic acid, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MsPPOH). Uterine arterial rings of these rats also dilated in response to MsPPOH. Furthermore, 5,6-EET could be metabolized to a thromboxane analog. In a bioassay, 5,6-EET increased the beating rate of neonatal cardiomyocytes. Blocking thromboxane synthesis reversed that finding and also normalized large-conductance calcium-activated potassium channel activity. CONCLUSIONS: Our data implicate CYP2J2 in the pathogenesis of preeclampsia and as a potential candidate for the disturbed uteroplacental remodeling, leading to hypertension and endothelial dysfunction. |
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Authors:
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Florian Herse; Babbette Lamarca; Carl A Hubel; Tea Kaartokallio; A Inkeri Lokki; Eeva Ekholm; Hannele Laivuori; Martin Gauster; Berthold Huppertz; Meryam Sugulle; Michael J Ryan; Sarah Novotny; Justin Brewer; Joon-Keun Park; Michael Kacik; Joachim Hoyer; Stefan Verlohren; Gerd Wallukat; Michael Rothe; Friedrich C Luft; Dominik N Muller; Wolf-Hagen Schunck; Anne C Staff; Ralf Dechend |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-15 |
Journal Detail:
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Title: Circulation Volume: 126 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-18 Completed Date: 2013-03-25 Revised Date: 2013-05-06 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 2990-9 Citation Subset: AIM; IM |
Affiliation:
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Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin, Germany. florian.herse@charite.de |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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8,11,14-Eicosatrienoic Acid
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analogs & derivatives*,
blood,
pharmacology Animals Cells, Cultured Cytochrome P-450 Enzyme System / analysis, genetics, physiology* Female Humans Hydrazines / pharmacology Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / physiology Oligonucleotide Array Sequence Analysis Placenta / blood supply Polymorphism, Single Nucleotide Pre-Eclampsia / blood, enzymology, etiology* Pregnancy Rats Rats, Sprague-Dawley |
| Grant Support | |
ID/Acronym/Agency:
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5M01RR00056/RR/NCRR NIH HHS; M01 RR000056/RR/NCRR NIH HHS; P01 HD030367/HD/NICHD NIH HHS; P01HD30367/HD/NICHD NIH HHS; R01 HD067541/HD/NICHD NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Hydrazines; 0/KCNMA1 protein, human; 0/Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; 7324-41-6/8,11,14-Eicosatrienoic Acid; 81246-84-6/5,6-epoxy-8,11,14-eicosatrienoic acid; 81276-03-1/14,15-epoxy-5,8,11-eicosatrienoic acid; 9035-51-2/Cytochrome P-450 Enzyme System; 98299-61-7/SQ 29548; EC 1.14.14.1/arachidonate epoxygenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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