Plenty Nicole L, Faulkner Jessica L, Cotton Joshua, Spencer Shauna-Kay, Wallace Kedra, LaMarca Babbette, Murphy Sydney R
Department of Obstetrics and Gynecology, Univ. of MS Medical Center, Jackson, MS, 39216, United States.
Department of Pharmacology, Univ. of MS Medical Center, Jackson, MS, 39216, United States.
Prostaglandins Other Lipid Mediat. 2018 May;136:15-22. doi: 10.1016/j.prostaglandins.2018.03.001. Epub 2018 Mar 26.
Few studies exist on cytochrome P450 (CYP450) metabolites of arachidonic acid (AA) pertaining to the pathophysiological events in pregnancy. We hypothesized that metabolism of AA via the CYP450 pathways is altered within the placenta in women with preeclampsia (PE) and contributes to the pathophysiology of the disease. Thus, placental vascular CYP450 enzyme expression and activity were measured in normal pregnant (NP) and preeclamptic (PE) patients. CYP450 isoform expression (CYP4A11, CYP4A22, CYP4F2, and CYP4F3) was found to be elevated within the placenta of women with PE compared to normal pregnant (NP) women and chronic hypertensive (CHTN) pregnant women. In addition, placental production of 20-HETE was significantly increased in PE women compared to both NP and CHTN women. Moreover, there was an imbalance in circulating 20-HETE:EETs in PE women. To examine whether alterations in CYP450 AA metabolism contribute to the altered placentation in PE, trophoblast function, proliferation and migration were assessed in the presence of exogenous 20-HETE and a 20-HETE specific synthesis inhibitor, HET0016. Trophoblast proliferation was significantly increased in the presence of 20-HETE (1 μM) and reduced with 20-HETE blockade by HET0016 (1 mM, 5 mM, and 10 mM). On the contrary, administration of exogenous 20-HETE (1 μM) significantly reduced trophoblast migration. In conclusion, metabolism of AA via CYP450 is altered in PE, and increased placental production of 20-HETE may contribute to the pathophysiology of the disease.
关于花生四烯酸（AA）的细胞色素P450（CYP450）代谢产物与妊娠病理生理事件的研究很少。我们假设，子痫前期（PE）女性胎盘内通过CYP450途径的AA代谢发生改变，并导致该疾病的病理生理过程。因此，我们测量了正常妊娠（NP）和子痫前期（PE）患者胎盘血管中CYP450酶的表达和活性。结果发现，与正常妊娠（NP）女性和慢性高血压（CHTN）妊娠女性相比，PE女性胎盘中CYP450同工型表达（CYP4A11、CYP4A22、CYP4F2和CYP4F3）升高。此外，与NP和CHTN女性相比，PE女性胎盘中20-羟基二十碳四烯酸（20-HETE）的产生显著增加。而且，PE女性循环中的20-HETE与环氧二十碳三烯酸（EETs）存在失衡。为了研究CYP450 AA代谢的改变是否导致PE中胎盘形成的改变，我们在存在外源性20-HETE和20-HETE特异性合成抑制剂HET0016的情况下评估了滋养层细胞的功能、增殖和迁移。在存在20-HETE（1μM）的情况下，滋养层细胞增殖显著增加，而HETOO16（1 mM、5 mM和10 mM）阻断20-HETE后增殖减少。相反，给予外源性20-HETE（1μM）显著降低了滋养层细胞的迁移。总之，PE中通过CYP450的AA代谢发生改变，胎盘20-HETE产生增加可能导致该疾病的病理生理过程。
