背景子痫前期,孕产妇和胎儿死亡率和发病率的主要原因,其特征是S-亚硝基化蛋白和活性氧的增加,提示在亚硝化和亚硝化应激中失调的病理生理作用。方法和结果,我们显示缺乏S-亚硝基谷胱甘肽还原酶(GSNOR-06-)的小鼠,一种调节蛋白S-亚硝基化的脱硝基酶,表现出先兆子痫表型,包括高血压,蛋白尿,肾脏病理学,心脏同心肥大,胎盘血管化减少,和胎儿生长迟缓.活性氧,NO,过氧亚硝酸盐水平升高。重要的是,质谱显示GSNOR-276-小鼠中胎盘S-亚硝基化氨基酸残基升高。除胎儿体重外,抗坏血酸逆转了表型,减少了S-亚硝基蛋白质组的差异,并在GSNOR-246-小鼠中鉴定出一组独特的S-亚硝基化蛋白。重要的是,人类先兆子痫胎盘表现出降低的GSNOR活性和增加的亚硝基应激。因此,结论,GSNOR的缺乏在小鼠中造成胎盘S-亚硝基化和先兆子痫的失调,可以用抗坏血酸来拯救。再加上在人类胎盘中的类似发现,这些发现为子痫前期提供了有价值的见解和治疗意义.
Background Preeclampsia, a leading cause of maternal and fetal mortality and morbidity, is characterized by an increase in S-nitrosylated proteins and reactive oxygen species, suggesting a pathophysiologic role for dysregulation in nitrosylation and nitrosative stress. Methods and Results Here, we show that mice lacking S-nitrosoglutathione reductase (GSNOR-⁄-), a denitrosylase regulating protein S-nitrosylation, exhibit a preeclampsia phenotype, including hypertension, proteinuria, renal pathology, cardiac concentric hypertrophy, decreased placental vascularization, and fetal growth retardation. Reactive oxygen species, NO, and peroxynitrite levels are elevated. Importantly, mass spectrometry reveals elevated placental S-nitrosylated amino acid residues in GSNOR-⁄- mice. Ascorbate reverses the phenotype except for fetal weight, reduces the difference in the S-nitrosoproteome, and identifies a unique set of S-nitrosylated proteins in GSNOR-⁄- mice. Importantly, human preeclamptic placentas exhibit decreased GSNOR activity and increased nitrosative stress. Conclusions Therefore, deficiency of GSNOR creates dysregulation of placental S-nitrosylation and preeclampsia in mice, which can be rescued by ascorbate. Coupled with similar findings in human placentas, these findings offer valuable insights and therapeutic implications for preeclampsia.