Sustained Endoplasmic Reticulum Stress as a Cofactor of Oxidative Stress in Decidual Cells from Patients with Early Pregnancy Loss

Abstract

Background: Oxidative stress is a common pathological background for different etiologies of early pregnancy loss (EPL). It has been suggested that elevated reactive oxygen species trigger endoplasmic reticulum (ER) stress by influencing ER function. However, it is unclear whether ER stress is associated with EPL. Objectives: The aim of the study was to determine whether and how ER stress occurs during the development of EPL. Approaches: Proteomic analysis was performed on decidua from women with EPL, and then ER stress markers, redox status, apoptotic features, and cell viability were analyzed in EPL decidual cells (DCs). Results: EPL decidua were characterized by decreased levels of glucose-regulated protein 78 (GPR78) and valosin-containing protein and burdened with ubiquitinated proteins. Evidence of ER stress-induced apoptosis in EPL DCs was demonstrated by extensive dilation of ER, morphological features of apoptosis, and activation of caspase-4 and caspase-12. Furthermore, H2O2 reduced the viabilities in both EPL and control DCs, whereas EPL DCs were more vulnerable to additional OS challenge than the controls as a result of failed induction of GRP78 expression. The cell survival percentages of DCs were dose-dependently reduced by H2O2 and could be reversed in the presence of vitamin E. This effect was partly mediated by reducing the amount of misfolded proteins rather than regulating GRP78 expression. Conclusions: The sum of these observations demonstrate for the first time that sustained ER stress occurs in EPL DCs and the potentially vicious relationship between ER stress and oxidative stress is likely to play an important role in the development of EPL.