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• W3000340081 abstract "Reactive oxygen species (ROS) have long been regarded as destructive molecules that have harmful effects. However, research data emerging over the last decade have demonstrated that ROS can positively influence a range of cellular events in a manner similar to that seen for traditional second messenger molecules. Hydrogen peroxide (H2O2) appears to be the main ROS with such signalling properties, and this molecule has been shown to affect a variety of cellular functions. Its synthesis by the NADPH oxidase (NOX) family of enzymes and how these enzymes are regulated in the human ovary are poorly investigated topics. In the ovary, ROS are involved in fundamental reproductive processes, as implicated by previous studies. However, ROS can also cause oxidative stress, which is associated with impaired oocyte quality and a negative outcome of assisted reproductive techniques. Oocytes grow and mature in ovarian follicles, formed by granulosa cells (GCs) and theca cells (TCs). NOX4, a member of the ROS-producing NOX family, was identified in cultured human in-vitro fertilization (IVF)-derived GCs as well as in corresponding GCs and TCs of growing preantral and antral follicles in human ovarian sections. It was further detected in GC- and TC-derived luteal cells of the corpus luteum. IVF-derived GCs resemble ovulatory GCs and/or the corpus luteum, but do not proliferate. Therefore, as a model for the growing follicle, the granulosa-like tumour cell line KGN was further studied. These cells also express NOX4.Accumulation of ROS in the medium of cultured GCs and KGN could be detected and was inhibited by the specific NOX4 blocker GKT137831. This blocker reduced specifically the production of H2O2 by around 45 % in GCs and KGN. This indicates a major contribution of NOX4 activity to the generation of H2O2. This is a rather long-lived and the only membrane-permeable ROS. H2O2 may diffuse to neighbouring cells, and studies implicated aquaporins in the uptake of extracellular H2O2 into GCs. The gonadotropins follicle stimulating hormone (FSH) and human chorionic gonadotropin (hCG) play a key role in reproduction. They induce the maturation of ovarian follicles, and the ovulation process. FSH and hCG, however, did not alter expression of NOX4, but elevated mRNA expression of antioxidant enzymes including catalase. This indicates a role of these hormones in ovarian ROS homeostasis. H2O2 and FSH also increased MAPK-phosphorylation, suggesting convergence of the signalling pathways. Furthermore, H2O2, when added to GCs, elevated several cytokines. This implicates H2O2 in inflammatory events, which are possibly involved in ovulation and/or regression of the corpus luteum. Inhibition of H2O2 production by GKT137831 did not affect cell viability of GCs but lowered expression of CYP11A1, a crucial enzyme for steroid synthesis. This suggests involvement in the maintenance of the steroidogenic phenotype of GCs. In proliferating KGN cells, GKT137831 reduced cell growth. This may implicate a role of H2O2 in cell proliferation and possibly in follicular growth. Taken together, the results imply important roles of H2O2 in the regulation of GCs. As ROS are potentially harmful molecules, the full elucidation of the two sides of the ROS-signalling system in the human ovary is important to guide future therapeutic strategies." @default.
• W3000340081 created "2020-01-23" @default.
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• W3000340081 date "2018-09-18" @default.
• W3000340081 modified "2023-09-24" @default.
• W3000340081 title "Role of ROS and ROS generating enzymes in the human ovary" @default.
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