17β-estradiol protects against oxidative stress-induced cell death through the glutathione/glutaredoxin-dependent redox regulation of Akt in myocardiac H9c2 cells

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 beta-estradiol (E-2), play an important role in development, growth, and differentiation and appear to have protective effects on oxidative stress mediated by estrogen receptor alpha( ER alpha). However, the role of the ER beta-mediated pathway in this cytoprotection and the involvement of E-2 in the redox regulation are not well understood. In the present study, we demonstrated that E-2 protected cardiac H9c2 cells, expressing ER beta from H2O2-induced apoptosis concomitant with an increase in the activity of Akt. E-2 induced the expression of glutaredoxin ( GRX) as well as gamma-glutamylcysteine synthetase, a rate-limiting enzyme for the synthesis of GSH. Inhibitors for both gamma-glutamylcysteine synthetase and GRX and ICI182,780, a specific inhibitor of ERs, abolished the protective effect of E-2 on cell survival as well as the activity of Akt, suggesting that ER beta is involved in the cytoprotection and redox regulation by E-2. Transcription of the GRX gene was enhanced by E-2. The promoter activity of GRX was up-regulated by an ER beta-dependent element. These results suggest that the GRX/GSH system is involved in the cytoprotective and genomic effects of E-2 on the redox state of Akt, a pathway that is mediated, at least in part, by ER beta. This mechanism may also play an antiapoptotic role in cancer cells during carcinogenesis or chemotherapy.