Abstract
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.
Highlights
Glutathione peroxidase 4 (Gpx4) is uniquely involved in the detoxification of oxidative damage to membrane lipids
Four selenoprotein glutathione peroxidases have been identified in mammalian systems: glutathione peroxidase 1 (Gpx1) was the first mammalian selenoprotein to be identified and is the most abundant glutathione peroxidase; glutathione peroxidase 2 (Gpx2) is a glutathione peroxidase expressed in the gastrointestinal tract; glutathione peroxidase 3 (Gpx3) is a plasma form of glutathione peroxidase; and glutathione peroxidase 4 (Gpx4) is a membrane-associated glutathione peroxidase that is called phospholipid hydroperoxide glutathione peroxidase
Tail DNA isolated from mice derived from the injected oocytes was digested with ScaI and probed with a 32P-labeled human GPX4 probe to detect the presence of human GPX4 gene (Fig. 1B)
Summary
Vol 279, No 53, Issue of December 31, pp. 55137–55146, 2004 Printed in U.S.A. Transgenic Mice Overexpressing Glutathione Peroxidase 4 Are Protected against Oxidative Stress-induced Apoptosis*. 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 Gpx 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. Embryonic fibroblasts derived from mice heterozygous for the Gpx gene (Gpx4ϩ/Ϫ) have increased lipid peroxidation, more cell death after exposure to oxidizing agents, and experienced growth retardation under high oxygen [13]. These data strongly suggest that Gpx deficiency makes cells vulnerable to oxidative stress, especially lipid peroxidation. The Tg(Gpx4) mouse is a potentially valuable animal model for studying the role of reduced membrane lipid peroxidation in vivo in the mechanism underlying a variety of pathological conditions
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