NADPH oxidase 4-mediating oxidative stress contributes to endometriosis

NADPH oxidase 4 (NOX4) plays an important role in the regulation of oxidative stress, which is associated with endometriosis. This study aims to investigate the effects of NOX4 in endometriosis and its molecular mechanisms. Clinical specimens were collected, and human endometrial stromal cells (HESCs) were isolated. The knockdown of NOX4 cell lines was established on the HESCs and induced by peritoneal fluid. The levels of NOX4 were determined by using immunohistochemistry (IHC) staining, western blotting, and qPCR, respectively. The levels of oxidative stress markers were determined by using western blotting and ELISAs, respectively. The correlation of NOX4 and oxidative stress markers was analyzed by the Pearson correlation coefficient. The levels of NOX4 were dramatically elevated in the ectopic endometrium. Besides, oxidative stress biomarkers were also dysregulated in the ectopic endometrium as compared to the normal endometrium. Pearson’s correlation coefficient analysis revealed a relationship between NOX4 and oxidative stress biomarkers in the ectopic endometrium. NOX4 modulated the expressions of oxidative stress markers in endometrial stromal cells stimulated by the peritoneal fluid from endometriosis. The effects of NOX4 on endometriosis are in part by its regulatory effects against oxidative stress. Similar content being viewed by others Data availability The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Amreen S, Kumar P, Gupta P, Rao P (2019) Evaluation of oxidative stress and severity of endometriosis. J Hum Reprod Sci 12(1):40 Basuroy S, Bhattacharya S, Leffler CW, Parfenova H (2009) Nox4 NADPH oxidase mediates oxidative stress and apoptosis caused by TNF-α in cerebral vascular endothelial cells. Am J Physiol Cell Physiol 296(3):C422–C432 Chen F, Haigh S, Barman S, Fulton DJ (2012) From form to function: the role of Nox4 in the cardiovascular system. Front Physiol 3:412 Cramer DW, Missmer SA (2002) The epidemiology of endometriosis. Ann N Y Acad Sci 955(1):11–22 Degasper C, Brunner A, Sampson N, Tsibulak I, Wieser V, Welponer H, Marth C, Fiegl H, Zeimet AG (2019) NADPH oxidase 4 expression in the normal endometrium and in endometrial cancer. Tumor Biol 41(2):1010428319830002 Donnez J, Binda MM, Donnez O, Dolmans M-M (2016) Oxidative stress in the pelvic cavity and its role in the pathogenesis of endometriosis. Fertil Steril 106(5):1011–1017 Draper HH, Hadley M (1990) [43] Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol Elsevier 186:421–431 Gupta S, Agarwal A, Krajcir N, Alvarez JG (2006) Role of oxidative stress in endometriosis. Reprod Biomed Online 13(1):126–134 Harlev A, Gupta S, Agarwal A (2015) Targeting oxidative stress to treat endometriosis. Expert Opin Ther Targets 19(11):1447–1464 Ighodaro O, Akinloye O (2018) First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alex J Med 54(4):287–293 Iwabuchi T, Yoshimoto C, Shigetomi H, Kobayashi H (2015) Oxidative stress and antioxidant defense in endometriosis and its malignant transformation. Oxid Med Cell Longev 2015:848595 Kashi AM, Moradi Y, Chaichian S, Najmi Z, Mansori K, Salehin F, Rastgar A, Khateri S (2018) Application of the World Health Organization quality of life instrument, short form (WHOQOL-BREF) to patients with endometriosis. Obstet Gynecol Sci 61(5):598–604 Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J (2010) NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart. Proc Natl Acad Sci 107(35):15565–15570 Lebovic DI, Mueller MD, Taylor RN (2001) Immunobiology of endometriosis. Fertil Steril 75(1):1–10 Murphy AA, Santanam N, Parthasarathy S (1998) Endometriosis: a disease of oxidative stress? Semin Reprod Endocrinol 16(4):263–73 Parasar P, Ozcan P, Terry KL (2017) Endometriosis: epidemiology, diagnosis and clinical management. Curr Obstet Gynecol Rep 6(1):34–41 Radermacher KA, Wingler K, Langhauser F, Altenhöfer S, Kleikers P, Hermans JR, Hrabě de Angelis M, Kleinschnitz C, Schmidt HH (2013) Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress. Antioxid Redox Signal 18(12):1418–1427 Rahiminejad ME, Moaddab A, Ganji M, Eskandari N, Yepez M, Rabiee S, Wise M, Ruano R, Ranjbar A (2016) Oxidative stress biomarkers in endometrial secretions: a comparison between successful and unsuccessful in vitro fertilization cycles. J Reprod Immunol 116:70–75 Santanam N, Kavtaradze N, Murphy A, Dominguez C, Parthasarathy S (2013) Antioxidant supplementation reduces endometriosis-related pelvic pain in humans. Transl Res 161(3):189–195 Scutiero G, Iannone P, Bernardi G, Bonaccorsi G, Padaro SS, Volta CA, Greco P, Nappi L (2017) Oxidative stress and endometriosis: a systematic review of the literature. Oxid Med Cell Longev 2017:7365238 Sorce S, Krause K-H (2009) NOX enzymes in the central nervous system: from signaling to disease. Antioxid Redox Signal 11(10):2481–2504 Streeter J, Thiel W, Brieger K, Miller J, Francis J (2013) Opportunity nox: the future of NADPH oxidases as therapeutic targets in cardiovascular disease. Cardiovasc Ther 31(3):125–137 Szukiewicz D, Stangret A, Ruiz-Ruiz C, Olivares EG, Soriţău O, Suşman S, Szewczyk G (2021) Estrogen-and progesterone (P4)-mediated epigenetic modifications of endometrial stromal cells (EnSCs) and/or mesenchymal stem/stromal cells (MSCs) in the etiopathogenesis of endometriosis. Stem Cell Rev Rep 17(4):1174–1193 Van Langendonckt A, Casanas-Roux F, Donnez J (2002) Oxidative stress and peritoneal endometriosis. Fertil Steril 77(5):861–870 Vendrov AE, Vendrov KC, Smith A, Yuan J, Sumida A, Robidoux J, Runge MS, Madamanchi NR (2015) NOX4 NADPH oxidase-dependent mitochondrial oxidative stress in aging-associated cardiovascular disease. Antioxid Redox Signal 23(18):1389–1409 Vercellini P, Viganò P, Somigliana E, Fedele L (2014) Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 10(5):261–275 Warzecha D, Szymusik I, Wielgos M, Pietrzak B (2020) The impact of endometriosis on the quality of life and the incidence of depression—a cohort study. Int J Env Res Public Health 17(10):3641 Yang H-L, Zhou W-J, Chang K-K, Mei J, Huang L-Q, Wang M-Y, Meng Y, Ha S-Y, Li D-J, Li M-Q (2017) The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β. Reproduction 154(6):815–825 Author information Authors and Affiliations Contributions All authors contributed to the study’s conception and design. Material preparation, data collection, and analysis were performed by Xiaojie Wang, Xiaona Jiang, Xin Lv, Xinshu Wang, and Aimin Lin. The first draft of the manuscript was written by Yangyang Li. All authors read and approved the final manuscript. Corresponding author Ethics declarations Ethics approval The study was approved by the Affiliated Yantai Yuhuangding Hospital of Qingdao University, and written informed consent was derived from each participant, the approval number is 2013–90. The study was performed in strict accordance with the Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects. Consent for publication Current study is available from the corresponding author on reasonable request. Conflict of interest statement The authors declare no competing interests. Additional information Communicated by Ewa Ziętkiewicz Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Wang, X., Jiang, X., Lv, X. et al. NADPH oxidase 4-mediating oxidative stress contributes to endometriosis. J Appl Genetics 65, 113–120 (2024). https://doi.org/10.1007/s13353-023-00810-7 Received: Revised: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s13353-023-00810-7