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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. 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. Reactive oxygen species (ROS), 1The abbreviations used are: ROS, reactive oxygen species; Gpx1–4, glutathione peroxidases 1–4; Tg(GPX4) mice, transgenic mice overexpressing Gpx4; t-BuOOH, t-butylhydroperoxide; ALT, alanine amino-transferase; cyt. c, cytochrome c; TEMED, N,N,N′, N′-tetramethylethylenediamine; PLA2, phospholipase A2; RT-PCR, reverse transcription-PCR; MEF, murine embryonic fibroblast; CL, cardiolipin; CLOOH, cardiolipin hydroperoxide. such as superoxide and hydrogen peroxide, are constantly generated in aerobic organisms during normal respiration. In addition, environmental factors (such as ionizing radiation) and pathological compounds (such as β-amyloid in Alzheimer's disease) can generate ROS. Although ROS at physiological concentrations may be required for normal cell function, excessive production of ROS can be detrimental to cells, because ROS can cause oxidative damage to lipids, protein, and DNA. Polyunsaturated fatty acids, which are found predominantly in cellular membranes, are especially vulnerable to attack by ROS because of the high concentration of allylic hydrogens in their structure (1Porter N.A. Caldwell S.E. Mills K.A. Lipid. 1995; 30: 277-290Crossref PubMed Scopus (1006) Google Scholar). The resulting lipid hydroperoxides can affect membrane fluidity and the function of membrane proteins. In addition, lipid hydroperoxides can undergo iron-mediated, one-electron reduction and oxygenation to form epoxyallylic peroxyl radicals, which trigger a chain reaction of free radical-mediated lipid peroxidation (2Girotti A.W. J. Lipid Res. 1998; 39: 1529-1542Abstract Full Text Full Text PDF PubMed Google Scholar). The end-products of lipid peroxidation are reactive aldehydes such as 4-hydroxyl nonenal and malondialdehyde, many of which are highly toxic to cells (3Yu B.P. Yang R. Ann. N. Y. Acad. Sci. 1996; 786: 1-11Crossref PubMed Scopus (157) Google Scholar). In addition, reactive aldehydes generated by lipid peroxidation can attack other cellular targets, such as proteins and DNA, thereby propagating the initial damage in cellular membranes to other macromolecules. Because lipid hydroperoxides formed in membranes are an important component of ROS generation in vivo, their detoxification appears to be critical in the survival of an organism to oxidative stress (4Mylonas C. Kouretas D. In Vivo. 1999; 13: 295-309PubMed Google Scholar, 5Dargel R. Exp. Toxicol. Pathol. 1992; 44: 169-181Crossref PubMed Scopus (217) Google Scholar). All cells possess a complex antioxidant system to detoxify reactive oxygen species. Antioxidant enzymes act in concert to remove various ROS produced by free radical reactions. Superoxide dismutases (Cu/Zn-SOD and Mn-SOD) scavenge the superoxide radicals, converting them into hydrogen peroxide and oxygen, whereas catalase and the glutathione peroxidases convert hydrogen peroxide to water. The glutathione peroxidases are a group of selenoproteins that catalyze the reduction of peroxides generated by ROS at the expense of glutathione (6Brigelius-Flohe R. Free Radic. Biol. Med. 1999; 27: 951-965Crossref PubMed Scopus (882) Google Scholar). 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 also called phospholipid hydroperoxide glutathione peroxidase. Recently, a new glutathione peroxidase, Gpx6, has been identified, but its cellular role and significance are not clear (7Kryukov G.V. Castellano S. Novoselov S.V. Lobanov A.V. Zehtab O. Guigo R. Gladyshev V.N. Science. 2003; 300: 1439-1443Crossref PubMed Scopus (1848) Google Scholar). Among the glutathione peroxidases, Gpx4 is unique in several ways. First, in addition to the common substrates (hydrogen peroxide and alkyl peroxides) reduced by all glutathione peroxidases, Gpx4 reduces hydroperoxide groups on phospholipids, lipoproteins, and cholesterol esters. Second, unlike the other glutathione peroxidases, which are tetrameric enzymes, Gpx4 is a monomeric enzyme and is rich in hydrophobic amino acid residues. Because of its small size and large hydrophobic surface, Gpx4 can interact with complex lipids in membranes and thereby detoxify membrane lipid hydroperoxides (8Ursini F. Bindoli A. Chem. Phys. Lipids. 1987; 44: 255-276Crossref PubMed Scopus (312) Google Scholar). The other pathway for removing membrane lipid peroxides from membranes is through the coupled actions of phospholipase A2 (PLA2) and Gpx1 (9van Kuijk F.J. Handelman G.J. Dratz E.A. J. Free Radic. Biol. Med. 1985; 1: 421-427Crossref PubMed Scopus (73) Google Scholar): PLA2 first excises the fatty acid hydroperoxide from the phospholipid hydroperoxide in the membrane, and then Gpx1 reduces the fatty acid hydroperoxide to alcohol and water. From kinetic modeling, the Gpx4 pathway is estimated to be far more efficient at removing phospholipid hydroperoxides than the PLA2-Gpx1 pathway, because the affinity of Gpx4 to membrane lipid peroxides is more than 104-fold greater than PLA2 (10Antunes F. Salvador A. Pinto R.E. Free Radic. Biol. Med. 1995; 19: 669-677Crossref PubMed Scopus (56) Google Scholar). Therefore, Gpx4 is considered to be the primary enzymatic defense system against oxidative damage to cellular membranes (6Brigelius-Flohe R. Free Radic. Biol. Med. 1999; 27: 951-965Crossref PubMed Scopus (882) Google Scholar). Gpx4 is ubiquitously expressed; however, its activity makes up only a fraction of the total cellular glutathione peroxidase activity in most tissues. The exception is the testes, where Gpx4 activity makes up the majority of the glutathione peroxidase activity (11Chambers I. Frampton J. Goldfarb P. Affara N. McBain W. Harrison P.R. J. PubMed Scopus Google Scholar). its cellular Gpx4 was to a critical role in the antioxidant defense system in using mice in The Gpx4 null mutation is at embryonic to A. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). In addition, embryonic fibroblasts from mice for the Gpx4 have lipid more cell death to and high oxygen W. A. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). These data that Gpx4 deficiency makes cells vulnerable to oxidative especially lipid 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, have elevated levels of Gpx4 (mRNA and protein) in all tissues that Tg(GPX4) mice had reduced oxidative oxidative The mouse is a for the role of reduced membrane lipid peroxidation in vivo in the mechanism a of pathological of Tg(GPX4) human was for the human GPX4 using a were for the of GPX4 and and by and using from the human data The clone the human GPX4 and of and from clone was and to from mice to generate transgenic mice by the of the was from mice from the with and by using a human GPX4 to the of the human GPX4 was to the mice The Tg(GPX4) mice were to mice and in the and mice at of were used for All for the mice in were and by the and of of at and the of for Gpx4 was from tissues using to the the of the human GPX4 was with using a of that the human GPX4 from human cell cells was used as for Gpx4 levels in tissues from Tg(GPX4) and wild type mice were as using a for and was used to for A. Res. 1998; PubMed Scopus Google Scholar). Gpx4 levels in tissues from Tg(GPX4) and wild type mice were by as A. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). Gpx4 in tissues and were in 1 and with The were at for at 4 to which were and to The resulting was then at for at 4 to the The was at for at 4 to the fraction and the containing Gpx4 levels in fraction were by levels for fraction were used to for for the for the for the mitochondrial and for the and from Tg(GPX4) and wild type mice were in in and for at at 4 The were used for antioxidant defense enzymatic activity Gpx1 activity was using activity as by Y. Free Radic. Res. PubMed Scopus Google Scholar). cell were on and the were in 1 reduced The hydroperoxide was to the and the were for The were with and in the with indicating the of glutathione peroxidase The were using a system and the data were using The activities of and were using a activity as Yang A. PubMed Scopus Google Scholar). of was on a The was then in a containing and The was at in a for the with indicating the of The were with a system and the were then using levels were by using an levels were used to for for Cell of of Tg(GPX4) and mice were to murine embryonic fibroblasts were from and in with and from were to in two and in as 1 The cells were as The of t-butylhydroperoxide and diquat were using the R. C. Res. PubMed Scopus Google Scholar). from Tg(GPX4) and wild type mice were in a at a concentration of were then to various concentrations of and diquat for 2 were in of and for 3 the of the of was to and the was for The was then to a and of the was at with a for caspase-3 activity in with was using the system from The cells were by and in in the Cell to of total were used to up caspase-3 activity reactions. at for the of in the reaction which were to caspase-3 activity present in the were with a at levels in tissues were by using an The of to of caspase-3 were and used as of caspase-3 and groups of Tg(GPX4) and wild type mice of were with diquat in at a of the mice were and plasma was to activity and free activities were using an The levels of were using as by and 1999; 300: PubMed Scopus Google Scholar). plasma was to and by for 3 4 the were from the clear with a and a The were then to and to The were to and the levels were by was to the at the of to of the The of was expressed as of of c and mitochondrial were as of were then on a to membranes, and to with an c were to for the for the mitochondrial of Tg(GPX4) on transgenic mice generated with a transgene containing human with large of the and that the mouse J. 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J. 2003; PubMed Scopus Google Scholar). human containing the human GPX4 3 and of and was identified and used to generate transgenic mice from mice from the was with and with a human GPX4 to the of human GPX4 lines of transgenic mice, Tg(GPX4) mice, were generated in are as and on by the mice to have of the and the Tg5 mice have of the transgene of Gpx4 in from Tg(GPX4) the of the human GPX4 total was from tissues of the Tg(GPX4) mice, and was using a of that the human GPX4 in human GPX4 is in and tissues from mice and Tg5 mice indicating that the human GPX4 transgene is expressed in Tg(GPX4) mice. from a human cell cells was used as a to demonstrate the of the Tg(GPX4) mice had levels of total Gpx4 from the and in and tissues using that were a to in Gpx4 levels in mice compared with wild type mice and a to in Gpx4 levels in Tg5 mice compared with wild type mice. the levels of Gpx4 were to levels of Gpx4 protein, the total Gpx4 levels in tissues from Tg(GPX4) mice were with an that the murine and human Gpx4 In mice, the levels of Gpx4 in testes, and of and were than in the tissues from wild type mice The total Gpx4 levels in tissues from Tg5 mice were to than their Because Gpx4 is with we compared the of Gpx4 in and of Tg5 and wild type mice. in was a to in Gpx4 in and from the of Tg5 mice. the Gpx4 appears to be in all in the Tg(GPX4) mice. Gpx4 and Gpx1 are two ubiquitously expressed selenoprotein glutathione to overexpression of Gpx4 the activity of Gpx1 in tissues of Tg(GPX4) mice. Therefore, we the Gpx1 activity in and from Tg(GPX4) and wild type mice. in was in Gpx1 activity in tissues from Tg5 transgenic mice. is an defense enzyme that hydrogen Therefore, we also catalase levels in tissues from wild and mice and found also the and activities in tissues from Tg(GPX4) and wild type mice, and we did not Tg5 and wild type mice and the overexpression of Gpx4 in of Tg(GPX4) mice had on the of the other antioxidant The studies that the GPX4 transgene is in all its is to the murine Gpx4 gene, we the transgene the null phenotype in the mice. that Gpx4 null at to A. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). In study, the mice, which Gpx4 at the were to mice for the murine Gpx4 to generate mice that have the human GPX4 mice. and mice were then and the were for the of the GPX4 as as for the of the mouse Gpx4 gene. an of the from two of new mice. was in mice that the human GPX4 is the of the from generated from mice were found in the mice. The of was to the indicating that the human GPX4 transgene can replace the Gpx4 in mice Gpx4 gene. These data also that the human GPX4 transgene was expressed during development. The mice into of and is in mice. of from Tg(GPX4) to Cell by were from wild type and Tg(GPX4) and from and Tg5 lines of Tg(GPX4) mice showed and in Gpx4 levels from wild type mice not Because is an that is to generate lipid peroxidation PubMed Scopus Google were to various concentrations of in that from Tg(GPX4) mice had significantly survival than from wild type mice to The data in also that from the Tg5 of Tg(GPX4) mice had survival than from to their levels of also compared the of from the Tg(GPX4) mice to superoxide by with the which superoxide J. Toxicol. Toxicol. PubMed Scopus Google Scholar). in from Tg(GPX4) mice had significantly survival than from wild type mice diquat from the Tg5 of Tg(GPX4) mice had survival than from the in cell survival was to the from the Tg(GPX4) mice reduced apoptosis in to we compared the activity of caspase-3 in from Tg(GPX4) mice and wild type mice. from Tg(GPX4) mice had a of caspase-3 activity compared with cells from wild type mice, and with caspase-3 activity in from Tg(GPX4) and wild type mice. caspase-3 activity was significantly in the from the Tg(GPX4) mice than from the wild type mice at 3 with the reduced cell death of from Tg(GPX4) mice appears to be with reduced of Tg(GPX4) to diquat is a that superoxide through J. Toxicol. Toxicol. PubMed Scopus Google Scholar). into mice, diquat damage with lipid peroxidation J. Exp. 1985; Google and diquat has been used to the role of antioxidant enzyme against oxidative stress in mice Y. Free Radic. Biol. Med. 1999; 27: PubMed Scopus Google Scholar). Therefore, we compared the of Tg(GPX4) and wild type mice to diquat levels of activity was as a of In mice, in plasma levels was Tg(GPX4) mice and wild type mice in a in plasma activity in wild type mice compared with a in the Tg(GPX4) mice. the Tg(GPX4) mice showed less damage in plasma in to diquat than wild type mice. also induced lipid peroxidation as by plasma levels J. Exp. Google Scholar). are a group of compounds that from free radical attack on membrane phospholipids, and the of is an of lipid peroxidation Ann. N. Y. Acad. Sci. PubMed Scopus Google Scholar). The data in that the plasma levels were in Tg(GPX4) mice and wild type however, diquat Tg(GPX4) mice had significantly levels of than wild type mice, indicating that diquat-induced lipid was reduced in the Tg(GPX4) mice. Because studies with overexpressing Gpx4 showed that reduced apoptosis was to reduced of cell death and because other showed cells with Gpx4 had a in apoptosis induced by a of oxidative N. Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, R. S. P. S. Full Text Full Text PDF PubMed Scopus Google Scholar, Free Radic. Biol. Med. 30: PubMed Scopus Google we the Tg(GPX4) mice showed reduced apoptosis in to diquat first the levels of caspase-3 in the of the mice, because is a important that is by of I. Cell Biol. 1999; PubMed Scopus Google and because its activation is a of The levels of caspase-3 in from wild type and Tg(GPX4) mice were by in diquat in of to caspase-3 was in in from Tg(GPX4) and wild type mice. diquat induced a in caspase-3 in from wild type mice and compared with a in Tg(GPX4) mice and appears that the Tg(GPX4) mice reduced apoptosis in diquat also cytochrome c release from in the diquat because cytochrome c release from is a important in the of apoptosis through the apoptosis in and diquat in an in cytochrome c in fraction of the of wild type and Tg(GPX4) mice. In wild type mice, was a in cytochrome c levels diquat was only a in cytochrome c levels in fraction of the of Tg(GPX4) mice also compared the cytochrome c levels in and diquat was of cytochrome c levels in of wild type mice diquat and of cytochrome c in fraction of from Tg(GPX4) mice was and cytochrome c release from into diquat was in tissues from Tg(GPX4) mice. In we the first mouse with a mutation in the Gpx4 A. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). The null mutation is at embryonic to Among the glutathione peroxidase mice have been generated for the and Gpx4 The phenotype of Gpx4 null mutation is more than the for null in the other glutathione mice null for the Gpx1 C. P. S. I. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google and J. normal normal to be more to oxidative mice for catalase were and mice null for catalase normal as Y. W. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). on of the of mice null for and catalase, which detoxify hydrogen peroxide and alkyl peroxides the glutathione but not the complex lipid hydroperoxides found in membranes, the embryonic lethal phenotype of Gpx4 mouse to the critical of Gpx4 in membrane lipid the several have the of overexpressing Gpx4 in various cell the overexpression of Gpx4 in and cells has been to D. A. N. Y. Res. 1996; PubMed Scopus Google Scholar, S. N. N. Res. 1996; PubMed Scopus Google Scholar). especially mitochondrial also has been to a role in the against lipid peroxidation and apoptosis are in cells overexpressing mitochondrial Gpx4 N. Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). cells overexpressing mitochondrial Gpx4 are to apoptosis induced by and but not to apoptosis induced by Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Gpx4 also apoptosis induced by in R. S. P. S. 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Although studies using mammalian cell lines overexpressing Gpx4 that Gpx4 can cells from oxidative stress and oxidative stress induced is on the of overexpressing Gpx4 in tissues of Therefore, we generated transgenic mice overexpressing Because Gpx4 is an human and mouse are transgenic mice were produced using the human GPX4 with large of the and Our data that the human GPX4 transgene is expressed in a that is to the mouse Gpx4 and that the human GPX4 transgene the lethal phenotype of the Gpx4 null Therefore, the of the human GPX4 transgene in the transgenic mice that we have generated appears to the of the murine Gpx4 gene. from Tg(GPX4) mice, we found that overexpression of Gpx4 survival oxidative stress compared with from wild type mice and that the survival was to reduced is with from previous using from mice in which we showed that from mice have reduced cell survival and apoptosis compared with from wild type mice oxidative stress W. A. Free Radic. Biol. Med. 2003; PubMed Scopus Google Scholar). also is with previous studies by other that the overexpression of Gpx4 is against oxidative in several cell N. Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, R. S. P. S. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. PubMed Scopus Google Scholar). studies with from the Tg(GPX4) mice to the we compared the of oxidative induced in the of Tg(GPX4) and wild type mice using a diquat a which superoxide through J. Toxicol. Toxicol. PubMed Scopus Google lipid peroxidation and damage in mice J. Exp. 1985; Google Scholar, Y. Free Radic. Biol. Med. 1999; 27: PubMed Scopus Google Scholar). found that the plasma a of lipid was significantly reduced in Tg(GPX4) mice compared with wild type mice. Gpx4 overexpression also reduced diquat-induced as by the reduced plasma activity of the of apoptosis the of Tg(GPX4) and wild type mice diquat we the activation of because caspase-3 is a of and its activation the of cells to apoptosis I. Cell Biol. 1999; PubMed Scopus Google Scholar). found caspase-3 in tissues of Tg(GPX4) and wild type mice. induced caspase-3 activation in Tg(GPX4) and wild type mice. the activation of caspase-3 was significantly less in Tg(GPX4) mice, a of caspase-3 in Tg(GPX4) mice a in wild type mice. Therefore, the Tg(GPX4) mice showed reduced apoptosis in diquat is the first that the overexpression of Gpx4 oxidative stress induced apoptosis in Because Gpx4 appears to from oxidative we the of overexpressing Gpx4 on the mitochondrial pathway of The release of cytochrome c from is a in the apoptosis by the activation of cyt. c is with cardiolipin PubMed Scopus Google a phospholipid found in the membrane that makes up the of the mitochondrial Because of its high of fatty acids, especially acid 1992; PubMed Scopus Google is to into cardiolipin hydroperoxide The of to has been to be a in the of apoptosis by the cardiolipin and cyt. c, resulting in the release of cyt. c from the Y. J. PubMed Scopus Google Scholar). Because Gpx4 has been in to to Y. J. PubMed Scopus Google the overexpression of Gpx4 to a reduction in apoptosis through a mechanism Gpx4 reduces the generated by oxidative stress and cyt. c from the and the mitochondria. have that cyt. c release from was attenuated in Tg(GPX4) mice. studies that Gpx4 a role in overexpression of Gpx4 has been to activities of and Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a showed that overexpression of Gpx4 induced the of in cells J. F. Res. Google Scholar). at levels in tissues of Tg(GPX4) transgenic mice diquat but did not not Gpx4 is also involved in and may affect R. F. A. P. F. J. 1998; PubMed Scopus Google Scholar, S. I. Y. Biol. PubMed Scopus Google Scholar). of Gpx4 be in Tg(GPX4) mice in In we have generated transgenic mice that Gpx4 in all tissues in a that the of the Gpx4 gene. Because the Tg(GPX4) mice alterations in the activities of the other antioxidant enzymes, especially Gpx1 and catalase, the primary phenotype of the Tg(GPX4) mice appears to be their to remove complex lipid hydroperoxides found in the mouse with a for the role of membrane lipid peroxidation in the of a of pathological and physiological data demonstrate that overexpression of Gpx4 the in vivo against apoptosis induced by oxidative stress through a mechanism that cyt. c release from through the detoxification of in mitochondrial
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