Increased epoxyeicosatrienoic acids and reduced soluble epoxide hydrolase expression in the preeclamptic placenta

Abstract

Background Epoxyeicosatrienoic acids (EETs) derived from cytochrome P450 (CYP)-dependent metabolism of arachidonic acid are increased in the plasma of women with preeclampsia as compared with normal pregnancy and are significantly higher in fetal than in maternal plasma and erythrocytes. We hypothesized that differences in EET synthesis or metabolism in the feto-placental unit contributed to the observed differences in circulating EETs. Method To evaluate EETs, formation as well as the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), biopsies of placenta were collected from 19 normal pregnancy and 10 preeclampsia at the time of cesarean section delivery. EETs were extracted from tissue homogenates and analyzed by liquid chromatography coupled with tandem mass spectrometry. Results Both cis-EETs and trans-EETs were detected in the placenta. Concentration of total EETs was higher in the placenta from preeclampsia compared with normal pregnancy (2.37 ± 1.42 ng/mg vs. 1.20 ± 0.72 ng/mg, mean ± SD, P < 0.01), especially the 5,6-, 8,9- and 11,12- EETs, measured in a subgroup of tissue samples (normal pregnancy = 10, preeclampsia = 5). By immunohistochemistry, sEH, CYP2J2, CYP4A11 were present in placental villi with different pattern distribution, whereas CYP2C8 was not detectable. Neither were CYP2J2, CYP4A11, and CYP2C8 detected in the umbilical cord. Western blot analysis of placenta homogenates showed reduced expression of sEH in preeclampsia as compared with normal pregnancy. Conclusion Increased EETs in the placenta and umbilical cord are associated with the presence of CYP2J2, whereas reduced expression of sEH in preeclampsia may be the key factor of increased EETs in the placenta.

Prediction and associations of preterm birth and its subtypes with eicosanoid enzymatic pathways and inflammatory markers

“…The impact that 5-oxoETE has on target sites can vary by cell type, but broadly involve intracellular changes that lead to heightened chemotaxis – an integral process that attracts immune cells to target tissues to drive the inflammatory process 18 . 5(6)-EET is a fatty acid metabolite of AA produced through the CYP450 pathway and commonly originates from the liver, kidneys, and vascular endothelium 19 . Importantly, 5(6)-EET is a modulator of cardiovascular function and predominantly acts as an anti-inflammatory vasodilator 19,20 .…”

“…5(6)-EET is a fatty acid metabolite of AA produced through the CYP450 pathway and commonly originates from the liver, kidneys, and vascular endothelium 19 . Importantly, 5(6)-EET is a modulator of cardiovascular function and predominantly acts as an anti-inflammatory vasodilator 19,20 . We observed protective associations between 5(6)-EET and spontaneous preterm birth, which aligns with the predominant paradigm of an anti-inflammatory and anti-hypertensive profile.…”

Application of an analytical framework for multivariate mediation analysis of environmental data

“…For example, epoxyeicosatrienoic acids (EETs) produced through the cytochrome p450 pathways are involved in vascular remodeling and regulation of inflammation 13 . Therefore these eicosanoids may be up-regulated in disease states involving cardiovascular irregularities, an important precursor for adverse pregnancy outcomes 14 . Among the environmental exposures, we also showed that phthalates have been associated with increased risk for preterm delivery and reduced gestational age at delivery within the LIFECODES cohort 15 , 16 .…”

Longitudinal profiles of plasma eicosanoids during pregnancy and size for gestational age at delivery: A nested case-control study

“…These lipid molecules are increasingly recognized as important vasoregulatory molecules and biomarkers involved in the pathophysiology of inflammation and oxidative stress [13,14]. There is growing evidence that eicosanoids are involved in a range of adverse pregnancy outcomes, including preeclampsia [15,16], preterm birth [17,18], and fetal growth disorders [19].…”