Sensitivity of mouse lung fibroblasts heterozygous for GPx4 to oxidative stress

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is a member of the family of selenium-dependent enzymes that catalyze the reduction of cell membrane-bound phospholipid hydroperoxides in situ and thus protects against membrane damage. Overexpression of GPx4 protects cultured cells from phosp...

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Bibliographic Details
Published in:Free radical biology & medicine 2008-03, Vol.44 (6), p.1075-1087
Main Authors: Garry, Michael R., Kavanagh, Terrance J., Faustman, Elaine M., Sidhu, Jaspreet S., Liao, Reiling, Ware, Carol, Vliet, Portia A., Deeb, Samir S.
Format: Article
Language:English
Subjects:
Adaptation, Physiological - physiology
Animals
Cardiolipin
Cardiolipins - metabolism
Cells, Cultured
Fibroblasts - metabolism
Glutathione Peroxidase - genetics
Glutathione Peroxidase - metabolism
GPX4
Heterozygote
Knockout mice
Lung - cytology
Lung - metabolism
Membrane Potential, Mitochondrial - physiology
Mice
Mice, Transgenic
Microscopy, Confocal
Mitochondrial membrane potential
Oxidation-Reduction
Oxidative stress
Oxidative Stress - physiology
PHGPx
Sulfhydryl Compounds - metabolism
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Summary:Phospholipid hydroperoxide glutathione peroxidase (GPx4) is a member of the family of selenium-dependent enzymes that catalyze the reduction of cell membrane-bound phospholipid hydroperoxides in situ and thus protects against membrane damage. Overexpression of GPx4 protects cultured cells from phosphatidylcholine hydroperoxide (PCOOH)-induced loss of mitochondrial membrane potential and blocks cell death induced by treatment with various apoptotic agents. We have generated mice that are heterozygous for a GPx4 null allele ( GPx4 +/-); the homozygous null genotype is embryonic lethal. We report that cultured lung fibroblasts (LFs) isolated from adult GPx4 +/- mice had approximately 50% of the GPx4 activity of LFs from GPx4 +/+ mice and were significantly more susceptible to H 2O 2, cadmium, and cumene hydroperoxide-induced cytotoxicity, as measured by neutral red assay. Both GPx4 +/+ and GPx4 +/- LFs were susceptible to PCOOH-induced cytotoxicity at a high PCOOH concentration. We also found that GPx4 +/- LFs have lower mitochondrial membrane potential, greater cardiolipin oxidation, and lower amounts of reduced thiols relative to GPx4 +/+ LFs, but are more resistant than GPx4 +/+ LFs to further decrements in these endpoints following PCOOH treatment. These results suggest that adult lung fibroblasts deficient in GPx4 may have upregulated compensatory mechanisms to deal with the highly oxidized environment in which they developed.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2007.12.002