Doridot Ludivine, Châtre Laurent, Ducat Aurélien, Vilotte Jean-Luc, Lombès Anne, Méhats Céline, Barbaux Sandrine, Calicchio Rosamaria, Ricchetti Miria, Vaiman Daniel
1 Department of Development, Reproduction, and Cancer, Institut Cochin , INSERM U1016, Paris, France .
Antioxid Redox Signal. 2014 Aug 20;21(6):819-34. doi: 10.1089/ars.2013.5661. Epub 2014 Jun 20.
Storkhead box 1 (STOX1) is a winged-helix transcription factor that is implicated in the genetic forms of a high-prevalence human gestational disease, pre-eclampsia. STOX1 overexpression confers pre-eclampsia-like transcriptomic features to trophoblastic cell lines and pre-eclampsia symptoms to pregnant mice. The aim of this work was to evaluate the impact of STOX1 on free radical equilibrium and mitochondrial function, both in vitro and in vivo.
Transcriptome analysis of STOX1-transgenic versus nontransgenic placentas at 16.5 days of gestation revealed alterations of mitochondria-related pathways. Placentas overexpressing STOX1 displayed altered mitochondrial mass and were severely biased toward protein nitration, indicating nitroso-redox imbalance in vivo. Trophoblast cells overexpressing STOX1 displayed an increased mitochondrial activity at 20% O2 and in hypoxia, despite reduction of the mitochondrial mass in the former. STOX1 overexpression is, therefore, associated with hyperactive mitochondria, resulting in increased free radical production. Moreover, nitric oxide (NO) production pathways were activated, resulting in peroxynitrite formation. At low oxygen pressure, STOX1 overexpression switched the free radical balance from reactive oxygen species (ROS) to reactive nitrogen species (RNS) in the placenta as well as in a trophoblast cell line.
In pre-eclamptic placentas, NO interacts with ROS and generates peroxynitrite and nitrated proteins as end products. This process will deprive the maternal organism of NO, a crucial vasodilator molecule.
Our data posit STOX1 as a genetic switch in the ROS/RNS balance and suggest an explanation for elevated blood pressure in pre-eclampsia.
鹳头盒蛋白1（STOX1）是一种翼状螺旋转录因子，与一种高发性人类妊娠疾病——先兆子痫的遗传形式有关。STOX1的过表达赋予滋养层细胞系先兆子痫样转录组特征，并使妊娠小鼠出现先兆子痫症状。本研究的目的是在体外和体内评估STOX1对自由基平衡和线粒体功能的影响。
对妊娠16.5天时的STOX1转基因胎盘与非转基因胎盘进行转录组分析，发现线粒体相关通路发生改变。过表达STOX1的胎盘线粒体质量发生改变，且严重偏向蛋白质硝化，表明体内存在亚硝基氧化还原失衡。过表达STOX1的滋养层细胞在20%氧气浓度下和缺氧条件下线粒体活性增加，尽管前者的线粒体质量有所减少。因此，STOX1的过表达与线粒体过度活跃有关，导致自由基产生增加。此外，一氧化氮（NO）生成途径被激活，导致过氧亚硝酸盐形成。在低氧压力下，STOX1的过表达使胎盘以及滋养层细胞系中的自由基平衡从活性氧（ROS）转变为活性氮（RNS）。
在先兆子痫胎盘中，NO与ROS相互作用，生成过氧亚硝酸盐和硝化蛋白质作为终产物。这一过程将使母体失去NO，一种关键的血管舒张分子。
我们的数据将STOX1定位为ROS/RNS平衡中的遗传开关，并为先兆子痫患者血压升高提供了解释。
