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.
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Abbreviations
- PCOS:
-
Polycystic ovary syndrome
- HIF-1a:
-
Hypoxia-inducible factor-1a
- ET-2:
-
Endothelin-2
- DMBG:
-
Dimethyldiguanide
- PHD:
-
HIF prolyl hydroxylase
- FSH:
-
Follicle-stimulating hormone
- LH:
-
Luteinizing hormone
- P4:
-
Progesterone
- E2:
-
Estrogen
- T:
-
Testosterone
- ELISA:
-
Enzyme-linked immunosorbent assay
- HPG axis:
-
Hypothalamus–pituitary–gonadal axis
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Acknowledgments
This work was supported by the National Natural Science Foundation of China (31101032 and 31271255), Program for New Century Excellent Talents in University of Ministry of Education of China (NCET-120614), Doctoral Foundation of the Ministry of Education in China (20113503120002) and Fujian Provincial Science and Technology Projects of the Department of Education (JB14041).
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Wang, F., Zhang, Z., Wang, Z. et al. Expression and clinical significance of the HIF-1a/ET-2 signaling pathway during the development and treatment of polycystic ovary syndrome. J Mol Hist 46, 173–181 (2015). https://doi.org/10.1007/s10735-015-9609-4
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DOI: https://doi.org/10.1007/s10735-015-9609-4