Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis.

Ran Q, Liang H, Gu M, Qi W, Walter CA, Roberts LJ, Herman B, Richardson A, Van Remmen H
J Biol Chem. 2004 279 (53): 55137-46

PMID: 15496407 · DOI:10.1074/jbc.M410387200

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.

MeSH Terms (38)

Alanine Transaminase Animals Antioxidants Apoptosis Blotting, Northern Blotting, Western Cardiolipins Caspase 3 Caspases Catalase Cells, Cultured Cell Survival Cytochromes c Diquat Dose-Response Relationship, Drug Enzyme Activation F2-Isoprostanes Female Fibroblasts Gene Library Glutathione Peroxidase Herbicides Humans Lipid Peroxidation Liver Male Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria Models, Genetic Oxidative Stress RNA RNA, Messenger Superoxide Dismutase tert-Butylhydroperoxide Tissue Distribution Transgenes

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