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.

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
• Journal: Circulation (Circulation) Vol. 126 Issue 25 Pg. 2990-9 (Dec 18 2012) ISSN: 1524-4539 [Electronic] United States
• PMID: 23155181 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• CYP2J2 protein, human
• Fatty Acids, Unsaturated
• Hydrazines
• KCNMA1 protein, human
• Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
• 5,6-epoxy-8,11,14-eicosatrienoic acid
• 14,15-epoxy-5,8,11-eicosatrienoic acid
• SQ 29548
• Cytochrome P-450 Enzyme System
• Cytochrome P-450 CYP2J2
• 8,11,14-Eicosatrienoic Acid

Topics

• 8,11,14-Eicosatrienoic Acid (analogs & derivatives, blood, pharmacology)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic
• Cells, Cultured
• Cytochrome P-450 CYP2J2
• Cytochrome P-450 Enzyme System (analysis, genetics, physiology)
• Fatty Acids, Unsaturated
• 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