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J. Biol. Chem., Vol. 279, Issue 53, 55137-55146, December 31, 2004

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Transgenic Mice Overexpressing Glutathione Peroxidase 4 Are Protected against Oxidative Stress-induced Apoptosis^*

Qitao Ran¶, Hanyu Liang¶||, Minjun Gu, Wenbo Qi, Christi A. Walter**, L. Jackson Roberts, II, Brian Herman, Arlan Richardson, and Holly Van Remmen¶¶

From the Department of Cellular and Structural Biology, the ^||Department of Physiology, the Barshop Center for Longevity and Aging Studies, and the ^**San Antonio Cancer Institute, the University of Texas Health Science Center at San Antonio, Texas 78229, the Geriatric Research, Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, Texas 78229, and the Departments of Pharmacology and Medicine, Vanderbilt University, Nashville, Tennessee 37232

Glutathione peroxidase 4 (Gpx4) is uniquely involved in the detoxification of oxidative damage to membrane lipids. Our previous studies showed that Gpx4 is essential for mouse survival and that Gpx4 deficiency makes cells vulnerable to oxidative injury. In the present study, we generated two lines of transgenic mice overexpressing Gpx4 (Tg(GPX4) mice) using a genomic clone containing the human GPX4 gene. Both lines of Tg-(GPX4) mice, Tg5 and Tg6, had elevated levels of Gpx4 (mRNA and protein) in all tissues investigated, and overexpression of Gpx4 did not cause alterations in activities of glutathione peroxidase 1, catalase, Cu/Zn superoxide dismutase, and manganese superoxide dismutase. The human GPX4 transgene rescued the lethal phenotype of null mutation of the mouse Gpx4 gene, indicating that the transgene can replace the essential role of mouse Gpx4 in mouse development. Cell death induced by t-butylhydroperoxide and diquat was significantly less in murine embryonic fibroblasts from Tg(GPX4) mice compared with wild type mice. Liver damage and lipid peroxidation induced by diquat were reduced significantly in Tg(GPX4) mice. In addition, diquat-induced apoptosis was decreased in Tg(GPX4) mice, as evidenced by attenuated caspase-3 activation and reduced cytochrome c release from mitochondria. These data demonstrate that Gpx4 plays a role in vivo in the mechanism of apoptosis induced by oxidative stress that most likely occurs through oxidative damage to mitochondrial phospholipids such as cardiolipin.

Received for publication, September 10, 2004 , and in revised form, October 20, 2004.

^* This work was supported by a Merit Review grant (to H. V. R.), an Environmental Hazards Center grant from the Department of Veteran Affairs (to H. V. R. and A. R.), and by National Institutes of Health Grants K01-AG22014 (to Q. R.), and P01-AG19316 (to A. R. and B. H.), and the Transgenic Core of the San Antonio Nathan Shock Aging Center (1P30-AG13319). 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.

^¶ Both authors contributed equally to this work.

^¶¶ To whom correspondence should be addressed: Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, GRECC 182, 7400 Merton Mintor Blvd., San Antonio, TX 78284. Tel.: 210-617-5300 (ext. 5673); Fax: 210-617-5312; E-mail: vanremmen{at}uthscsa.edu.

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