Heme induced progesterone-resistant profiling and promotion of endometriosis in vitro and in vivo

Endometriosis is an estrogen-dependent, progesterone-resistant gynecological disease with an unknown pathogenesis. Compared to women without endometriosis, women with endometriosis have a remarkably high heme level in the peritoneal fluid. To further investigate the pathomechanisms of heme in endome...

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Published in:Biochimica et biophysica acta. Molecular basis of disease 2023-10, Vol.1869 (7), p.166761-166761, Article 166761
Main Authors: Ma, Xiao-Qian, Liu, Yu-Yin, Zhong, Zhi-Qi, Chen, Si-Man, Hu, Wen-Ting, Sheng, Yan-Ran, Liu, Yu-Kai, Wei, Chun-Yan, Li, Ming-Qing, Zhu, Xiao-Yong
Format: Article
Language:English
Subjects:
Endometriosis
Heme
Migration
Mitochondria
Oxidative phosphorylation (OXPHOS)
Progesterone resistance
Proliferation
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Summary:Endometriosis is an estrogen-dependent, progesterone-resistant gynecological disease with an unknown pathogenesis. Compared to women without endometriosis, women with endometriosis have a remarkably high heme level in the peritoneal fluid. To further investigate the pathomechanisms of heme in endometriosis, we aimed to identify the dysregulated expression of heme-trafficking proteins, such as PGRMC1/2 that are also receptors that mediate the non-genomic responses to progesterone, and heme-degrading enzymes between ectopic endometrial stromal cells and their normal counterparts. We found that heme could regulate progesterone receptor-related gene expression. Functional human endometrial stromal cell experiments showed that heme promotes cell proliferation and migration in a heme oxygenase-1-independent manner; moreover, blocking oxidative phosphorylation/ATP generation could abolish these effects of heme in vitro, whereas intraperitoneal hemopexin administration could alleviate heme-triggered ectopic lesions in vivo. Therefore, heme likely mediates the induction of progesterone resistance and simultaneously induces endometriosis via the mitochondrial oxidative phosphorylation pathway. •Heme down-regulates PGRMC2 expression at transcription and translation levels.•Free heme at the same level as in peritoneal fluid enhanced proliferation and migration function of HESCs.•Pro-proliferative and pro-migratory effects of heme depend on ROS induction as an intact molecule.•Hemopexin administration weakened endometriosis growth in mice model.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2023.166761