Dalle Vedove Francesco, Fava Cristiano, Jiang Houli, Zanconato Giovanni, Quilley John, Brunelli Matteo, Guglielmi Valeria, Vattemi Gaetano, Minuz Pietro
aDepartment of Medicine, Verona, Italy bDepartment of Pharmacology, New York Medical College, Valhalla, New York, USA cDepartment of Surgical Sciences, Dentistry, Gynecology and Pediatrics dDepartment of Diagnostics and Public Health eDepartment of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy *These authors contributed equally to the study.
J Hypertens. 2016 Jul;34(7):1364-70. doi: 10.1097/HJH.0000000000000942.
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.
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.
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.
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.
与正常妊娠相比，子痫前期女性血浆中由细胞色素P450（CYP）依赖的花生四烯酸代谢产生的环氧二十碳三烯酸（EETs）增加，且胎儿血浆和红细胞中的EETs显著高于母体。我们推测，胎儿-胎盘单位中EET合成或代谢的差异导致了循环EETs的观察差异。
为了评估EETs的形成以及相关CYP同工型和代谢酶可溶性环氧化物水解酶（sEH）的表达，在剖宫产时从19例正常妊娠和10例子痫前期患者中采集胎盘组织活检样本。从组织匀浆中提取EETs，并通过液相色谱-串联质谱法进行分析。
在胎盘中检测到顺式EETs和反式EETs。子痫前期胎盘组织中总EETs浓度高于正常妊娠（2.37±1.42 ng/mg vs. 1.20±0.72 ng/mg，平均值±标准差，P<0.01），特别是在一组组织样本中测量的5,6-、8,9-和11,12-EETs（正常妊娠=10例，子痫前期=5例）。通过免疫组织化学方法，sEH、CYP2J2、CYP4A11在胎盘绒毛中呈现不同的模式分布，而未检测到CYP2C8。在脐带中也未检测到CYP2J2、CYP4A11和CYP2C8。胎盘匀浆的蛋白质免疫印迹分析显示，与正常妊娠相比，子痫前期sEH的表达降低。
胎盘和脐带中EETs的增加与CYP2J2的存在有关，而子痫前期sEH表达降低可能是胎盘中EETs增加的关键因素。
