HIF1A-induced heme oxygenase 1 promotes the survival of decidual stromal cells against excess heme-mediated oxidative stress

Author:

Shen Hui-Hui1,Wang Cheng-Jie1,Zhang Xin-Yan1,Sheng Yan-Ran1,Yang Shao-Liang1,Zheng Zi-Meng1,Shi Jia-Lu1,Qiu Xue-Min12,Xie Feng3,Li Ming-Qing145ORCID

Affiliation:

1. 1Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

2. 2Clinical Research Center, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China

3. 3Medical Center of Diagnosis and Treatment for Cervical and Intrauterine Diseases, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, People’s Republic of China

4. 4Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, People’s Republic of China

5. 5Department of Obstetrics and Gynecology, Maternal and Child Health Hospital of Longgang District, Shenzhen, Guangdong Province, People’s Republic of China

Abstract

Heme oxygenase 1 (HO-1, encoded by the HMOX1 gene) is the rate-limiting enzyme that catalyzes heme degradation, and it has been reported to exert antioxidative effects. Recently, decidualization has been reported to confer resistance to environmental stress signals, protecting against oxidative stress. However, the effects and regulatory mechanism of HO-1 in decidual stromal cells (DSCs) during early pregnancy remain unknown. Here, we verified that the levels of HO-1 and heme in DSCs are increased compared with those in endometrial stromal cells. Additionally, the upregulation of HIF1A expression led to increased HMOX1 expression in DSCs possibly via nuclear factor erythroid 2-related factor (encoded by the NFE2L2 gene). However, addition of the competitive HO-1 inhibitor zinc protoporphyrin IX resulted in an increase in HIF1A expression. Hydrogen peroxide (H2O2) induced the production of reactive oxygen species (ROS), decreased the cell viability of DSCs in vitro, and upregulated the level of heme. As an HO-1 inducer, cobalt protoporphyrin IX decreased ROS production and significantly reversed the inhibitory effect of H2O2 on cell viability. More importantly, patients with unexplained spontaneous abortion had low levels of HO-1 that were insufficient to protect against oxidative stress. This study suggests that the upregulation of HO-1 expression via HIF1A protects DSCs against excessive heme-mediated oxidative stress. Furthermore, the excessive oxidative stress injury and impaired viability of DSCs associated with decreased HO-1 expression should be associated with the occurrence and/or development of spontaneous abortion.

Publisher

Bioscientifica

Subject

Cell Biology,Obstetrics and Gynecology,Endocrinology,Embryology,Reproductive Medicine

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