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J. Biol. Chem., Vol. 281, Issue 19, 13092-13102, May 12, 2006

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17-Estradiol Protects against Oxidative Stress-induced Cell Death through the Glutathione/Glutaredoxin-dependent Redox Regulation of Akt in Myocardiac H9c2 Cells^*

Yoshishige Urata¹², Yoshito Ihara¹, Hiroaki Murata, Shinji Goto, Takehiko Koji, Junji Yodoi^¶, Satoshi Inoue^||, and Takahito Kondo

From the Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan, the Department of Histology and Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan, the ^¶Department of Biological Responses, Institute for Viral Research, Graduate School of Medicine, Kyoto University, 53 Shogoin, Kawahara-cho, Sakyo-ku, Kyoto 606-8397, Japan, and the ^||Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

The GSH/glutaredoxin (GRX) system is involved in the redox regulation of certain enzyme activities, and this system protects cells from H₂O₂-induced apoptosis by regulating the redox state of Akt (Murata, H., Ihara, Y., Nakamura, H., Yodoi, J., Sumikawa, K., and Kondo, T. (2003) J. Biol. Chem. 278, 50226–50233). Estrogens, such as 17-estradiol (E₂), play an important role in development, growth, and differentiation and appear to have protective effects on oxidative stress mediated by estrogen receptor (ER). However, the role of the ER-mediated pathway in this cytoprotection and the involvement of E₂ in the redox regulation are not well understood. In the present study, we demonstrated that E₂ protected cardiac H9c2 cells, expressing ER from H₂O₂-induced apoptosis concomitant with an increase in the activity of Akt. E₂ induced the expression of glutaredoxin (GRX) as well as -glutamylcysteine synthetase, a rate-limiting enzyme for the synthesis of GSH. Inhibitors for both -glutamylcysteine synthetase and GRX and ICI182,780, a specific inhibitor of ERs, abolished the protective effect of E₂ on cell survival as well as the activity of Akt, suggesting that ER is involved in the cytoprotection and redox regulation by E₂. Transcription of the GRX gene was enhanced by E₂. The promoter activity of GRX was up-regulated by an ER-dependent element. These results suggest that the GRX/GSH system is involved in the cytoprotective and genomic effects of E₂ on the redox state of Akt, a pathway that is mediated, at least in part, by ER. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy.

Received for publication, March 1, 2006

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Health, Labor, and Welfare of Japan (H15-Choju-015), by the Technology through the 21st Century Center of Excellence program, and by a research grant for health sciences from the Japanese Ministry of Health and Welfare. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AF167981 [GenBank] , BC063166 [GenBank] , NM_001101 [GenBank] .2, AY280663 [GenBank] .1, U57439 [GenBank] , NM_000125 [GenBank] .2, and NM_001437 [GenBank] .1.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Tel.: 81-95-849-7099; Fax: 81-95-849-7100; E-mail: urata{at}net.nagasaki-u.ac.jp.

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