ABSTRACT
Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.
Subject(s)
Amine Oxidase (Copper-Containing)/metabolism , Cell Adhesion Molecules/metabolism , Endometriosis/metabolism , Peritoneal Diseases/metabolism , Aldehydes/metabolism , Allyl Compounds/pharmacology , Amine Oxidase (Copper-Containing)/antagonists & inhibitors , Analgesics/pharmacology , Animals , Biomarkers/metabolism , Cell Adhesion Molecules/antagonists & inhibitors , Disease Models, Animal , Endometriosis/genetics , Endometriosis/pathology , Female , Gene Expression Profiling , Heme/metabolism , Humans , Inflammation Mediators/metabolism , Interleukin-8/metabolism , Iron/metabolism , Lipid Peroxidation , Metabolic Networks and Pathways , Mice , Mice, Inbred BALB C , Myeloid Cells/pathology , Oxidative Stress , Peritoneal Diseases/genetics , Peritoneal Diseases/pathology , Phagocytosis , Sulfonamides/pharmacologyABSTRACT
An amendment to this paper has been published and can be accessed via a link at the top of the paper.