title: OS066. Intrauterine CYP2J2 expression and circulatingepoxyeicosatrienoic acid levels in preeclampsia.
abstract: BACKGROUND
  The cytochrome P450 (CYP)-system regulates vascular functions, inflammation, and angiogenesis that are mechanistically important in preeclampsia.
  
  
  OBJECTIVE
  The aim of this study was to analyze the dysregulation of the Cytochrome P450 in the pathogenesis of preeclampsia.
  
  
  METHODS
  We performed microarray screening of placenta and decidua from 25 preeclamptic women and 23 controls. Results were confirmed by realtime RT-PCR, immunohistochemistry and Serum of patients were analyzed by HPLC tandem mass spectrometry. For functional testing we did cardiomyocyte contraction bioassay and myograph studies. The reduced uterine perfusion pressure (RUPP) rat model was proceed for interventional study.
  
  
  RESULTS
  In microarray studies the CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic decidual tissue (3.9 fold, p<0.0001) and in preeclamptic placenta (1.55 fold, p<0.001). RT-PCR confirmed the upregulation and immunohistochemistry, localized CYP2J2 in trophoblasts of villi and deciduas at week 12 and term. The CYP2J2 metabolites were analyzed by HPLC tandem mass spectrometry. 5,6- epoxyeicosatrienoic acids (EET), 14,15-EET, and the corresponding dihydroxyeicosatrienoic acids (DHET), were elevated in preeclamptic women compared to controls in the latter two-thirds of pregnancy and after delivery. Stimulation of the trophoblast-derived cell line SGHPL-4 with the preeclampsia-associated cytokine tumor necrosis factor-a enhanced CYP2J2 gene and protein expression. For functional testing, 5,6-EET increased the beating rate of neonatal cardiomyocytes in a bioassay and downregulated large-conductance calcium-activated potassium channel KCa 1.1 activity. In the RUPP rat model of preeclampsia, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP inhibitor MsPPOH. Uterine arterial rings of rats also dilated in response to MsPPOH.
  
  
  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, Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Herse
authors.affiliation: Department of Obstetrics and Gynecology, University of Mississippi Medical Center, Jackson, United States.
authors.forename: B B
authors.initials: BB
authors.lastname: LaMarca
authors.affiliation: Magee-Womens Research Institute, Pittsburgh, United States.
authors.forename: C A
authors.initials: CA
authors.lastname: Hubel
authors.affiliation: University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Laivuori
authors.affiliation: Medical University of Graz, Graz, Austria.
authors.forename: B
authors.initials: B
authors.lastname: Huppertz
authors.affiliation: Charité University Medicine Berlin, Berlin, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Verlohren
authors.affiliation: Experimental and Clinical Research Center, Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: D N
authors.initials: DN
authors.lastname: Muller
authors.affiliation: Max-Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: W H
authors.initials: WH
authors.lastname: Schunck
authors.affiliation: Department of Obstetrics and Gynaecology, Oslo University Hospital, HELIOS-Klinik, Berlin, Germany.
authors.forename: A C
authors.initials: AC
authors.lastname: Staff
authors.affiliation: Experimental and Clinical Research Center, HELIOS-Klinik, Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Dechend