CYP2J2 Expression and Circulating Epoxyeicosatrienoic Metabolites in Preeclampsia

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 erlohren;
Gerd Wallukat; Michael Rothe; Friedrich C. Luft; Dominik N. Muller; Wolf-Hagen Schunck; Anne Cathrine Staff; Ralf Dechend

CIRCULATIONAHA.112.127340

Published online before print November 15, 2012,

Abstract

Background—Preeclampsia is a multisystem disorder of pregnancy, originating in the placenta. Cytochrome P450 (CYP)-dependent eicosanoids regulate vascular function, inflammation, and angiogenesis that are mechanistically important in preeclampsia.

Methods and Results—We performed microarray screening of placenta and decidua (maternal placenta) from 25 preeclamptic women and 23 controls. The CYP subfamily 2J polypeptide 2 (CYP2J2) was upregulated in preeclamptic placenta and decidua. RT-PCR confirmed the upregulation and immunohistochemistry localized CYP2J2 in trophoblastic villi and deciduas at 12 weeks and term. The CYP2J2 metabolites, 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. Stimulating a trophoblast-derived cell line with the preeclampsia-associated cytokine, tumor necrosis factor-α enhanced CYP2J2 gene and protein expression. In two independent rat models of preeclampsia, reduced uterine-perfusion rat and the transgenic Ang II rat, we observed elevated EET, DHET, and preeclamptic features that were ameliorated by the CYP epoxygenase inhibitor, 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 (KCa1.1) 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.