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: Fan Wang, Zhenghong Zhang, Zhaokai Wang, Kaizhuan Xiao, Qing Wang, Jingqian Su, Zhengchao Wang
• Journal: Journal of molecular histology (J Mol Histol) Vol. 46 Issue 2 Pg. 173-81 (Apr 2015) ISSN: 1567-2387 [Electronic] Netherlands
• PMID: 25613530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aromatase Inhibitors
• Biguanides
• Endothelin-2
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit

Topics

• Animals
• Aromatase Inhibitors (pharmacology, therapeutic use)
• Biguanides (pharmacology, therapeutic use)
• Drug Evaluation, Preclinical
• Endothelin-2 (genetics, metabolism)
• Female
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Ovary (drug effects, metabolism, pathology)
• Polycystic Ovary Syndrome (drug therapy, metabolism)
• Rats, Sprague-Dawley
• Signal Transduction