Cytochrome P450 Subfamily 2J Polypeptide 2 Expression and Circulating Epoxyeicosatrienoic Metabolites in Preeclampsia

Article

关键词: TUMOR-NECROSIS-FACTOR;    UTERINE PERFUSION-PRESSURE;    EPOXYGENASE-DERIVED EICOSANOIDS;    ARACHIDONIC-ACID;    ANGIOTENSIN-II;    PREGNANT RATS;    PLACENTAL ISCHEMIA;    CARDIOVASCULAR-DISEASE;    CHRONIC REDUCTIONS;    HYPERTENSION;   

DOI  :  10.1161/CIRCULATIONAHA.112.127340

来源: SCIE

【 摘 要 】

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-alpha 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. (Circulation. 2012;126:2990-2999.)

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