The Unfolded Protein Response Regulates Uterine Myocyte Antioxidant Responsiveness During Pregnancy

Abstract

There is considerable evidence that implicates oxidative stress in the pathophysiology of human pregnancy complications. However, the role and the mechanism of maintaining an antioxidant prosurvival uterine environment during normal pregnancy is largely unresolved. Herein we report that the highly active uterine unfolded protein response plays a key role in promoting antioxidant activity in the uterine myocyte across gestation. The unfolded protein response (UPR) senses the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and activates a signaling network that consists of the transmembrane protein kinase eukaryotic translation initiation factor 2 alpha kinase 3/PKR-like-ER kinase (EIF2AK3), which acts to decrease protein translation levels, allowing for a lowered need for protein folding during periods of ER stress. However, independent of its translational regulatory capacity, EIF2AK3-dependent signals elicit the activation of the transcription factor, nuclear factor erythroid 2-like 2 (NFE2L2) in response to oxidative stress. NFE2L2 binds to antioxidant response elements in the promoters of a variety of antioxidant genes that minimize the opportunities for generation of reactive oxygen intermediates. Our analysis demonstrates that in the absence of EIF2AK3, the uterine myocyte experiences increased levels of reactive oxygen species due to decreased NFE2L2 activation. Elevated levels of intracellular reactive oxygen species were observed in the EIF2AK3 null cells, and this was associated with the onset of apoptotic cell death. These findings confirm the prosurvival and antioxidant role of UPR-mediated EIF2AK3 activation in the context of the human uterine myocyte.

The effect of gestational age on mitochondrial properties of the mouse placenta

“…It was found that genes Eif2ak3 and Eif4g1 both decreased as gestation proceeded. In the absence of Eif2AK3 , other studies have found cells to experience increased oxidative stress, leading to cell death ( Ramnarayanan et al 2016 ). Although this study did not measure markers of oxidative stress directly, we indirectly established increases in superoxide production across gestation through decreases in the antioxidant activity of SOD, which may indicate that there was an increase of ROS at E16.5.…”

MicroRNA profiling associated with muscle growth in modern broilers compared to an unselected chicken breed

“…It plays a critical role in neutralizing oxidative stress by activating the expression of antioxidants and detoxifying enzymes [ 45 ]. The activation of EIF2AK3 and GSTT1 genes is associated with decreased level of reactive oxygen species [ 46 , 47 ]. Previously, the augmentation of the NRF2-mediated oxidative stress response pathway is observed in breast muscle of higher feed efficient and rapidly growing chickens [ 48 ].…”