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Transgenic mice overexpressing glutathione peroxidase 4 are protected against oxidative stress-induced apoptosis.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2004 Dec 31; Vol. 279 (53), pp. 55137-46. Date of Electronic Publication: 2004 Oct 20. - Publication Year :
- 2004
-
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.
- Subjects :
- Alanine Transaminase blood
Animals
Antioxidants pharmacology
Blotting, Northern
Blotting, Western
Cardiolipins metabolism
Caspase 3
Caspases metabolism
Catalase metabolism
Cell Survival
Cells, Cultured
Cytochromes c metabolism
Diquat pharmacology
Dose-Response Relationship, Drug
Enzyme Activation
F2-Isoprostanes blood
Female
Fibroblasts metabolism
Gene Library
Glutathione Peroxidase metabolism
Herbicides pharmacology
Humans
Lipid Peroxidation
Liver metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitochondria metabolism
Models, Genetic
Phospholipid Hydroperoxide Glutathione Peroxidase
RNA metabolism
RNA, Messenger metabolism
Superoxide Dismutase metabolism
Tissue Distribution
Transgenes
tert-Butylhydroperoxide pharmacology
Glutathione Peroxidase GPX1
Apoptosis
Glutathione Peroxidase biosynthesis
Oxidative Stress
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 279
- Issue :
- 53
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15496407
- Full Text :
- https://doi.org/10.1074/jbc.M410387200