title: Cytochrome P450 subfamily 2J polypeptide 2 expression and circulating epoxyeicosatrienoic metabolites in preeclampsia.
abstract: 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.
  
  
  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.affiliation: Experimental and Clinical Research Center, Lindenberger Weg 80, 13125 Berlin, Germany. florian.herse@charite.de
authors.forename: Florian
authors.initials: F
authors.lastname: Herse
authors.forename: Babbette
authors.initials: B
authors.lastname: Lamarca
authors.forename: Carl A
authors.initials: CA
authors.lastname: Hubel
authors.forename: Tea
authors.initials: T
authors.lastname: Kaartokallio
authors.forename: A Inkeri
authors.initials: AI
authors.lastname: Lokki
authors.forename: Eeva
authors.initials: E
authors.lastname: Ekholm
authors.forename: Hannele
authors.initials: H
authors.lastname: Laivuori
authors.forename: Martin
authors.initials: M
authors.lastname: Gauster
authors.forename: Berthold
authors.initials: B
authors.lastname: Huppertz
authors.forename: Meryam
authors.initials: M
authors.lastname: Sugulle
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ryan
authors.forename: Sarah
authors.initials: S
authors.lastname: Novotny
authors.forename: Justin
authors.initials: J
authors.lastname: Brewer
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Michael
authors.initials: M
authors.lastname: Kacik
authors.forename: Joachim
authors.initials: J
authors.lastname: Hoyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Verlohren
authors.forename: Gerd
authors.initials: G
authors.lastname: Wallukat
authors.forename: Michael
authors.initials: M
authors.lastname: Rothe
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Wolf-Hagen
authors.initials: WH
authors.lastname: Schunck
authors.forename: Anne C
authors.initials: AC
authors.lastname: Staff
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002478:Cells, Cultured; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D005231:Fatty Acids, Unsaturated; D005260:Female; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000098:blood supply; D020641:Polymorphism, Single Nucleotide; D011225:Pre-Eclampsia / Q000097:blood / Q000201:enzymology / Q000209:etiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; C000717350:CYP2J2 protein, human; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; C040776:5,6-epoxy-8,11,14-eicosatrienoic acid; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; C045749:SQ 29548; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid