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

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

  • Biochim Biophys Acta Mol Basis Dis. 2023 May 27;166761. doi: 10.1016/j.bbadis.2023.166761.
Xiao-Qian Ma 1,  Yu-Yin Liu 2,  Zhi-Qi Zhong 3,  Si-Man Chen 1,  Wen-Ting Hu 1,  Yan-Ran Sheng 1,  Yu-Kai Liu 1,  Chun-Yan Wei 1,  Ming-Qing Li 4,  Xiao-Yong Zhu 5
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Shanghai Medical College of Fudan University, Shanghai 200011, People's Republic of China; Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China.
  • 2 Department of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510510, People's Republic of China.
  • 3 Xinglin College, Nantong University, Nantong 226001, People's Republic of China.
  • 4 Department of Obstetrics and Gynecology, Shanghai Medical College of Fudan University, Shanghai 200011, People's Republic of China; Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China. Electronic address: mqli@fudan.edu.cn.
  • 5 Department of Obstetrics and Gynecology, Shanghai Medical College of Fudan University, Shanghai 200011, People's Republic of China; Institute of Obstetrics and Gynecology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China; Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200080, People's Republic of China. Electronic address: zhuxiaoyong@fudan.edu.cn.
PMID: 37247698 DOI: 10.1016/j.bbadis.2023.166761
Abstract

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.

Keywords

Endometriosis; Heme; Migration; Mitochondria; Oxidative phosphorylation (OXPHOS); Progesterone resistance; Proliferation.

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