title: 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.
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Saiprasad
authors.initials: S
authors.lastname: Ramnarayanan
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Chandrashekara
authors.initials: C
authors.lastname: Kyathanahalli
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Judith
authors.initials: J
authors.lastname: Ingles
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan.
authors.forename: MieJung
authors.initials: M
authors.lastname: Park-York
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan.|Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan.|Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
authors.forename: Pancharatnam
authors.initials: P
authors.lastname: Jeyasuria
authors.affiliation: Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Detroit, Michigan jcondon@med.wayne.edu.|Department of Physiology, School of Medicine, Wayne State University, Detroit, Michigan.|Perinatology Research Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Condon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D004717:Endometrium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D011247:Pregnancy; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000502:physiology*; D014599:Uterus / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; C460640:EIF2AK3 protein, human; D019892:eIF-2 Kinase
keywords: oxidative stress; pregnancy; unfolded protein response; uterus