Document Detail


Cytochrome P450 subfamily 2J polypeptide 2 expression and circulating epoxyeicosatrienoic metabolites in preeclampsia.
MedLine Citation:
PMID:  23155181     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-15
Journal Detail:
Title:  Circulation     Volume:  126     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-18     Completed Date:  2013-03-25     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2990-9     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
8,11,14-Eicosatrienoic Acid / 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:
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:
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
Comments/Corrections

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