Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions

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.Endometriosis, affecting 5-10% of women in reproductive age, is a gynaecological disease characterized by the presence of ectopic endometrial tissue most often found in the pelvic cavity 1,2 . Retrograde menstruation is a widely accepted pathogenic mechanism for the formation of peritoneal lesions, in which uterine epithelial and stromal cells are disseminated during menstruation and implanted into the peritoneal cavity via the Fallopian tubes 3,4 . Peritoneal lesions are macroscopically classified based on colour, appearing as white, red, brown, or black lesions. This appearance seems to be determined by endometrial gland content and a variable adjacent stromal reaction, likely reflecting a chronicity process rather than different levels of disease activity 5 . Additional contributors to disease such as genetic, epigenetic and environmental factors exist, since a majority (90%) of women undergo retrograde menstruation associated with successful clearance of menstrual debris from the peritoneal cavity 3,6-9 . However, the formation of ectopic endometrial lesions is a signature event that leads to the hallmarks of disease, comprising sustained inflammation, severe and chronic pain, as well as subfertility 10,11 . www.nature.com/scientificreports www.nature.com/scientificreports/ proteomic and transcriptomic arms of the study distinct patient populations were used and further collection details are provided in the SI material.Protein extraction and sample preparation. Tissue material was homogenised and extracted, protein extracts were subjected to in-solution trypsin digestion and data processed as described 51 . Transcriptome analysis. Illumina compatible next-generation sequencing libraries were prepared and sequenced from ribosomal RNA depleted or...

Inflammatory Mediators and Pain in Endometriosis: A Systematic Review

“…Interestingly, there are several evidences that IL-8 cytokine facilitates the migration of fibroblasts and endothelial cells [ 57 ]. In endometriosis, the IL-8 levels are increased under the synthesis of the oxidative stress products (e.g., 4-hydroxy-2-nonenal) [ 58 ].…”

Molecular and Clinical Insights on the Complex Interaction between Oxidative Stress, Apoptosis, and Endobiota in the Pathogenesis of Endometriosis

“…In this regard, it was shown that several inflammation-related molecules are also regulated dependently or independently of ROS production and accumulation. Thézénas et al [29] identified amine oxidase 3 and vascular adhesion protein 1 (AOC3/VAP1), in particular alkenal reductase PTGR1 and methionine sulfoxide reductase, as candidates for altered ROS landscape in EMS and possibly influencing the systemic and/or local inflammatory response. Furthermore, they observed important molecular changes in the ectopic lesion (such as iron overload, increased ROS production, and lipid peroxidation) and noted that ROS-derived 4-hydroxy-2-nonenal (4-HNE) over-production led to monocytic interleukin IL-8 release.…”

Novel Diagnostic Markers for Endometriosis

“…Due to the multitude of factors regulating the level of oxidative stress, authors highlight that there is need of further studies to conclude if there is possible use of oxidative stress markers as diagnostic tests for endometriosis [9,44].…”