Li C, Raikwar N S, Santillan M K, Santillan D A, Thomas C P
Department of Obstetrics and Gynecology, Iowa City, IA, USA.
Division of Nephrology, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Placenta. 2015 Apr;36(4):446-53. doi: 10.1016/j.placenta.2015.01.004. Epub 2015 Jan 17.
Elevated circulating soluble FLT1 (sFLT1) levels seen in preeclampsia may play a role in its development. Aspirin is recommended for prevention of preeclampsia. We hypothesized that aspirin may inhibit the production of sFlt1.
Placentas from women with and without preeclampsia were collected. Primary cytotrophoblasts (CTBs) were cultured from normal placentas and treated with aspirin, sc-560, a COX1 inhibitor or celecoxib, a COX2 inhibitor. The expression of sFLT1, FLT1, COX1 and COX2 was studied. The effect of aspirin on sFlt1 expression was also studied in HEK293 cells and in HTR-8/SVNeo cells.
The expression of sFLT1 was increased in preeclamptic placentas compared to control placentas and the expression and release of sFLT1 increased in CTBs exposed to 2% O2 compared to controls. Aspirin at 3 and 12 mM concentration reduced the expression and release of sFLT1 in CTBs. Aspirin also inhibited sFlt1 expression from HTR-8/SVNeo and HEK293 cells. Sc-560, but not celecoxib, reduced sFLT1 expression and release from CTBs. Aspirin and sc-560 also reduced hypoxia-induced FLT1 mRNA expression and inhibited COX1 mRNA in CTBs.
This study confirms that sFLT1 expression is increased in preeclamptic placentas and in CTBs exposed to hypoxia. Aspirin inhibits the production sFLT1 in CTBs and in HTR-8/SVNeo. Sc-560 recapitulated the effects of aspirin on sFLT1 expression and release in CTBs suggesting that the aspirin effect may be mediated via inhibition of COX1. The study increases our understanding of the mechanisms regulating sFlt1 expression and provides a plausible explanation for the effect of aspirin to prevent preeclampsia.
子痫前期患者循环中可溶性FLT1（sFLT1）水平升高可能在其发病过程中起作用。推荐使用阿司匹林预防子痫前期。我们推测阿司匹林可能抑制sFlt1的产生。
收集患子痫前期和未患子痫前期女性的胎盘。从正常胎盘中培养原代细胞滋养层细胞（CTB），并用阿司匹林、COX1抑制剂sc-560或COX2抑制剂塞来昔布进行处理。研究sFLT1、FLT1、COX1和COX2的表达。还在HEK293细胞和HTR-8/SVNeo细胞中研究了阿司匹林对sFlt1表达的影响。
与对照胎盘相比，子痫前期胎盘sFLT1的表达增加，与对照组相比，暴露于2%氧气的CTB中sFLT1的表达和释放增加。3 mM和12 mM浓度的阿司匹林可降低CTB中sFLT1的表达和释放。阿司匹林还抑制HTR-8/SVNeo和HEK293细胞中sFlt1的表达。Sc-560可降低CTB中sFLT1的表达和释放，但塞来昔布无此作用。阿司匹林和sc-560还可降低缺氧诱导的CTB中FLT1 mRNA表达并抑制COX1 mRNA。
本研究证实子痫前期胎盘和暴露于缺氧环境的CTB中sFLT1表达增加。阿司匹林抑制CTB和HTR-8/SVNeo中sFLT1的产生。Sc-560在CTB中重现了阿司匹林对sFLT1表达和释放的影响，表明阿司匹林的作用可能是通过抑制COX1介导的。该研究增加了我们对调节sFlt1表达机制的理解，并为阿司匹林预防子痫前期的作用提供了合理的解释。
