Abstract
Although many previous studies have suggested that estrogen functions as a cytoprotective agent under oxidative stress conditions, the underlying mechanism by which this effect is exerted remains to be elucidated. This study assessed the effects of estradiol-17β (E2) (10−8 M) on hypoxia-induced cell injury and its related signaling in primary cultured chicken hepatocytes. Hypoxic conditions were found to augment the level of DNA damage and to reduce cell viability and the level of [3H]-thymidine incorporation, and these phenomena were prevented through treatment with E2. Hypoxia also increased caspase-3 expression, but showed no evidence of an influence on the expression of Bcl-2. However, E2 induced an increase in the level of Bcl-2 expression under hypoxic conditions and reduced the level of caspase-3 expression. The effects of E2 on Bcl-2 and caspase expression were blocked by ICI 182780 (E2 receptor (ER) antagonist, 10−7 M). In addition, hypoxia resulted in an increase in the intracellular reactive oxygen species (ROS) generated. These effects were blocked by E2, but not by E2-BSA and ICI 182780. Hypoxia also activated p38 mitogen-activated protein kinase (MAPK), c-JUN N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and nuclear factor-κB (NF-κB). These effects were blocked by E2, but not by ICI 182780. The inhibition of p38 MAPK and JNK/SAPK blocked NF-κB activation. In conclusion, E2 was found to protect against hypoxia-induced cell injury in chicken hepatocytes through ER-mediated upregulation of Bcl-2 expression and through reducing the activity of ROS-dependent p38 MAPK, JNK/SAPK and NF-κB.
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Acknowledgements
This work was supported by a grant (NO. 20050301-034-487-007-0300) from the Biogreen 21 Program, Rural Development Administration, Republic of Korea. The authors acknowledge a graduate fellowship provided by the Ministry of Education and Human Resources Development through the Brain Korea 21 Project, Republic of Korea.
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Lee, M., Jung, S., Lee, J. et al. Estradiol-17β protects against hypoxia-induced hepatocyte injury through ER-mediated upregulation of Bcl-2 as well as ER-independent antioxidant effects. Cell Res 18, 491–499 (2008). https://doi.org/10.1038/cr.2008.42
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DOI: https://doi.org/10.1038/cr.2008.42
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