Aberrant reactive aldehyde detoxification by aldehyde dehydrogenase-2 influences endometriosis development and pain-associated behaviors

• Type of Material: Article
• Authors: Stacy McAllister, Emory University; Pritam Sinharoy, Stanford University School of Medicine; Megana Vasu, Stanford University School of Medicine; Eric R. Gross, Stanford University School of Medicine
• Language: English
• Date: 2021-01-01
• Publisher: Wolters Kluwer Health, Inc.
• Publication Version: Final Published Version
• Copyright Statement: © 2020 The Author(s).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1097/j.pain.0000000000001949
• Title of Journal or Parent Work: Pain
• Volume: 162
• Issue: 1
• Start Page: 71
• End Page: 83
• Grant/Funding Information: All work on this project and research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under Award Number R00HD093858 (SLM) and National Institute of General Medical Sciences GM119522 (ERG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University, Department of Obstetrics and Gynecology at Emory University, an Endometriosis Foundation of America Research Award, and a Stanford Women’s Health and Sex Differences in Medicine Seed Grant.; Tissue samples were provided by the NIH P50 National Centers in Translational Research in Reproduction (NCTRI) Human Endometrial Tissue Bank and DNA Bank at UCSF, funded under NIH HD055764 (LCG).
• Keywords: Pain; Endometriosis; Mitochondria; Aldehyde Dehydrogenase, Mitochondrial; Humans; Female; Animals; Aldehydes; Mice
• Research Categories: Health Sciences, Obstetrics and Gynecology

Abstract

Endometriosis affects ∼176 million women worldwide, yet on average, women experience pain ∼10 years from symptom onset before being properly diagnosed. Standard treatments (drugs or surgery) often fail to provide long-term pain relief. Elevated levels of reactive aldehydes such as 4-hydroxynonenal (4-HNE) have been implicated in the peritoneal fluid of women with endometriosis and upon accumulation, reactive aldehydes can form protein-adducts and/or generate pain. A key enzyme in detoxifying reactive aldehydes to less reactive forms is the mitochondrial enzyme aldehyde dehydrogenase-2 (ALDH2). Here, we tested the hypothesis that aberrant reactive aldehyde detoxification by ALDH2 underlies endometriosis and its associated pain. We determined, in the eutopic and ectopic endometrium of women with severe (stage IV) peritoneal endometriosis, that ALDH2 enzyme activity was decreased, which was associated with decreased ALDH2 expression and increased 4-HNE adduct formation compared to the eutopic endometrium of controls in the proliferative phase. Using a rodent model of endometriosis and an ALDH2*2 knock-in mouse with decreased ALDH2 activity, we determined that increasing ALDH2 activity with the enzyme activator Alda-1 could prevent endometriosis lesion development as well as alleviate pain-associated behaviors in proestrus. Overall, our findings suggest that targeting the ALDH2 enzyme in endometriosis may lead to better treatment strategies and in the proliferative phase, that increased 4-HNE adduct formation within the endometrium may serve as a less invasive diagnostic biomarker to reduce years of suffering in women.