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.
Highlights
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]
No difference was observed between normal endometrium from controls and from eutopic endometrium in endometriosis patients, suggesting that the implantation of endometrium and development of lesions leads to a significant change in the proteome
Tryptophan and cysteine modifications showed no significant difference between ectopic lesions and controls, and oxidation and formylation levels for histidine, tryptophan and cysteine were generally low in ectopic lesions and controls
Summary
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]. LPP detoxifying enzymes such as aldehyde dehydrogenase 2 (ALDH2) could possibly shield the organism from endogenously damaging LPPs arising from lipid peroxidation under oxidative stress[20,21,22]. This is indirectly supported by epidemiological evidence describing an ALDH2 polymorphism in Asians, pointing towards a potential role of ALDH2 in pain prevalence and pain tolerance, threshold, or intensity[23,24,25]. Our interest in target discovery in endometriosis instigated a systematic proteomic approach, further supported by transcriptomics, to identify in greater depth the potential underlying reasons for upregulated oxidative stress and its possible consequences
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