title: Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome.
abstract: Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway may be an important mechanism regulating PCOS formation and treatment in mammalian ovaries in vivo and should be a new clinical target for PCOS prevention and treatment in the future.
authors.affiliation: Provincial Key Laboratory for Developmental Biology and Neurosciences, College of Life Sciences (Qishan Campus), Fujian Normal University, 8, Shangsan Road, Fuzhou, 350007, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhaokai
authors.initials: Z
authors.lastname: Wang
authors.forename: Kaizhuan
authors.initials: K
authors.lastname: Xiao
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Jingqian
authors.initials: J
authors.lastname: Su
authors.forename: Zhengchao
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D001645:Biguanides / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D019333:Endothelin-2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D047072:Aromatase Inhibitors; D001645:Biguanides; D019333:Endothelin-2; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit