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 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. Conclusion 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.

Interfering with Gal-1–mediated angiogenesis contributes to the pathogenesis of preeclampsia

“…For analyses of Gal-1 levels, patient samples from the research bio-bank collection at Oslo University Hospital, Oslo, approved by the Regional Committee of Medical Research Ethics in Eastern Norway, were used as described (40). The clinical characteristics of the human cohort are summarized in SI Materials and Methods and Table S3.…”

Functional studies of N‐terminally modified CYP2J2 epoxygenase in model lipid bilayers

“…11 Hence, the development of drugs inhibiting CYP2J2 has tremendous pharmaceutical potential for the prevention of cancer metastasis and preeclampsia. 11,14,17,18 CYP2J2 also plays an important role in the first-pass metabolism of astemizole, terfenadine, and ebastine and is essential for understanding the pharmacokinetic and pharmacodynamic relationships of these drugs in the body. 17,19 Thus, to begin to elucidate the structure-function relationships of pharmaceutically relevant CYP2J2, we expressed the protein with high yields in Escherichia coli and focused on understanding the role of the N-terminus of CYP2J2 in association with lipid bilayers and in ebastine hydroxylation activity.…”

Functional changes in the uterine artery precede the hypertensive phenotype in a transgenic model of hypertensive pregnancy

“…Similarly, in the preeclamptic placenta, TXA 2 production is increased more than three times compared with normal placentas (33), an effect proposed to be mediated by increased reactive oxygen species generation (34), suggesting that greater TXA 2 levels may mediate systemic vascular alterations in preeclampsia. Recent reports also support the contribution of CYP epoxygenase to the effects on blood pressure, albuminuria, and vascular function observed in the TgA rat at late gestation (17). Thus human and animal studies support the role of eicosanoids in the uteroplacental and systemic pathological changes in preeclampsia.…”

“…In TgA rats, a role for thromboxane (32) and 5,6-epoxyeicosatrienoic acid (17) in modulating vascular responses has been described at late gestation, and increased CYP epoxygenase expression has been proposed as a contributor to vascular dysfunction in this model (17). It is conceivable that circulating cytotoxic factors released by hypoperfusion and hypoxia caused by defective placentation in this model of preeclampsia would increase the expression of eicosanoid-generating pathways.…”