Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30044 (antioxidant enzyme)
 8,037 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lipid peroxidation has been implicated in a variety of pathophysiological processes, including inflammation, atherogenesis, neurodegeneration, and the ageing process. Phospholipid hydroperoxide glutathione peroxidase (GPX4) is the only major antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha tocopherol (vitamin E) to inhibit lipid peroxidation. Here we describe the generation and characterization of GPX4-deficient mice by targeted disruption of the murine Gpx4 locus through homologous recombination in embryonic stem cells. Gpx4(-/-) embryos die in utero by midgestation (E7.5) and are associated with a lack of normal structural compartmentalization. Gpx4(+/-) mice display reduced levels of Gpx4 mRNA and protein in various tissues. Interestingly, cell lines derived from Gpx4(+/-) mice are markedly sensitive to inducers of oxidative stress, including gamma-irradiation, paraquat, tert-butylhydroperoxide, and hydrogen peroxide, as compared to cell lines derived from wild-type control littermates. Gpx4(+/-) mice also display reduced survival in response to gamma-irradiation. Our observations establish GPX4 as an essential antioxidant enzyme in mice and suggest that it performs broad functions as a component of the mammalian antioxidant network.
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PMID:The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. 1256 75

Chronic exposure of male rats to the alkylating agent cyclophosphamide, a well-known male-mediated developmental toxicant, alters gene expression in male germ cells as well as in early preimplantation embryos sired by cyclophosphamide-exposed males. Sperm DNA is organized by the nuclear matrix into loop-domains in a sequence-specific manner. In somatic cells, loop-domain organization is involved in gene regulation. Various structural and functional components of the nuclear matrix are targets for chemotherapeutic agents. Consequently, we hypothesized that cyclophosphamide treatment would alter the expression of sperm nuclear matrix proteins. Adult male rats were treated for 4 wk with saline or cyclophosphamide (6.0 mg kg(-1) day(-1)), and the nuclear matrix was extracted from cauda epididymal sperm. Proteins were analyzed by two-dimensional gel electrophoresis. Identified proteins within the nuclear matrix proteome were mainly involved in cell structure, transcription, translation, DNA binding, protein processing, signal transduction, metabolism, cell defense, or detoxification. Interestingly, cyclophosphamide selectively induced numerous changes in cell defense and detoxification proteins, most notably, in all known forms of the antioxidant enzyme glutathione peroxidase 4, in addition to an uncharacterized 54-kDa form; an overall increase in glutathione peroxidase 4 immunoreactivity was observed in the nuclear matrix extracts from cyclophosphamide-exposed spermatozoa. An increase in glutathione peroxidase 4 expression suggests a role for this enzyme in maintaining nuclear matrix stability and function. These results led us to propose that a change in composition of the nuclear matrix in response to drug exposure was a factor in altered sperm function and embryo development.
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PMID:Chronic cyclophosphamide exposure alters the profile of rat sperm nuclear matrix proteins. 1747 30

Glutathione peroxidase 4 (Gpx4) is a unique antioxidant enzyme that repairs oxidative damage to biomembranes. In this study, we examined the effects of Gpx4 on the release of various apoptogenic proteins from mitochondria using transgenic mice overexpressing Gpx4 [Tg(GPX4(+/0))] and mice deficient in Gpx4 (Gpx4+/- mice). Diquat exposure triggered apoptosis that occurred through an intrinsic pathway and resulted in the mitochondrial release of cytochrome c (Cyt c), Smac/DIABLO, and Omi/HtrA2 in the liver of wild-type (Wt) mice. Liver apoptosis and Cyt c release were suppressed in Tg(GPX4(+/0)) mice but exacerbated in Gpx4+/- mice; however, neither the Tg(GPX4(+/0)) nor the Gpx4+/- mice showed any alterations in the levels of Smac/DIABLO or Omi/HtrA2 released from mitochondria. Submitochondrial fractionation data showed that Smac/DIABLO and Omi/HtrA2 existed primarily in the intermembrane space and matrix, whereas Cyt c and Gpx4 were both associated with the inner membrane. In addition, diquat exposure induced cardiolipin peroxidation in the liver of Wt mice; the levels of cardiolipin peroxidation were reduced in Tg(GPX4(+/0)) mice but elevated in Gpx4+/- mice. These data suggest that Gpx4 differentially regulates apoptogenic protein release owing to its inner membrane location in mitochondria and its ability to repair cardiolipin peroxidation.
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PMID:Glutathione peroxidase 4 differentially regulates the release of apoptogenic proteins from mitochondria. 1944 73

Twenty-six Angus-cross cows were used to examine the effect of BW loss (WL) on skeletal muscle and erythrocyte markers of oxidative stress. Serum NEFA concentrations, erythrocyte superoxide dismutase, and glutathione peroxidase activities were measured during WL and BW maintenance. Real-time reverse-transcription-PCR was used to determine mRNA levels of antioxidant genes during both periods to assess skeletal muscle response to WL. Body weight loss resulted in elevated serum NEFA concentrations but no change in erythrocyte superoxide dismutase and glutathione peroxidase activities. During WL, mRNA levels of the antioxidant genes glutathione peroxidase 4, mitochondrial superoxide dismutase, thioredoxin reductase 1, and selenoprotein W increased. Abundance of mRNA of genes involved in antioxidant signaling, specifically, PPARgamma coactivator-1 alpha, nuclear respiratory factor 1, estrogen-related receptor alpha, and tumor protein 53, was also increased. In summary, during WL cows had no change in peripheral antioxidant enzyme activity, but mRNA abundance of proteins involved in protecting the body from oxidative stress increased in skeletal muscle. During times when NEFA are used as a fuel source, signals such as mild reactive oxygen species production or increased concentration of lipid by-products activate the transcription of nuclear signaling molecules such as PPARgamma gamma coactivator-1 alpha, nuclear respiratory factor 1, estrogen-related receptor alpha, and tumor protein 53. These genes work to activate antioxidant genes such as mitochondrial superoxide dismutase, glutathione peroxidase 4, and thioredoxin reductase 1 to aid in the detoxification of reactive oxygen species. These data suggest an important role for antioxidant genes to protect cattle that are mobilizing body fat.
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PMID:Body weight loss in beef cows: II. Increased antioxidant messenger ribonucleic acid levels in skeletal muscle but not erythrocyte antioxidant activity. 1946 95

Glutathione peroxidase 4 (Gpx4) is an essential antioxidant enzyme having multiple functions. A long form Gpx4 protein and a short form Gpx4 protein, which are distinguishable by the presence or lack of a mitochondrial signal peptide at the N terminus, are generated from the Gpx4 gene. In this study, we generated transgenic mice using mutated GPX4 genes encoding either the long form Gpx4 (lGPX4 gene) or the short form Gpx4 (sGPX4 gene). Our results showed that transgenic mice with the sGPX4 gene had increased Gpx4 protein in all tissues and were protected against diquat-induced apoptosis in liver. Moreover, the sGPX4 gene was able to rescue the lethal phenotype of the mouse Gpx4-null mutation. In contrast, transgenic mice with the lGPX4 gene had increased Gpx4 protein only in the testes, and the lGPX4 gene failed to rescue the lethal phenotype of the mouse Gpx4-null mutation. In Gpx4-null mice rescued by the sGPX4 gene, the Gpx4 protein was present in mitochondria isolated from somatic tissues, and the submitochondrial distribution pattern of the Gpx4 protein in these mice was identical to that in wild-type mice. Interestingly, the male Gpx4-null mice rescued by the sGPX4 gene were infertile and exhibited sperm malformation. Together, our results demonstrated for the first time that the short form Gpx4 protein is present in somatic tissue mitochondria and is essential for survival and protection against apoptosis in mice, whereas the long form Gpx4 protein is important for male fertility.
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PMID:Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. 1974 30

Numerous studies characterizing the function of glutathione peroxidase 4 (GPx4) have demonstrated that this selenoenzyme is protective against oxidative stress. Herein, we characterized the function of this protein by targeting GPx4 downregulation using RNA interference. Partial knockdown of GPx4 levels resulted in growth retardation and morphological changes. Surprisingly, GPx4 knockdown cells showed virtually unchanged levels of intracellular ROS, yet highly increased levels of oxidized lipid by-products. GPx1, another glutathione peroxidase and a major cellular peroxide scavenging enzyme, did not rescue GPx4-deficient cells and did not reduce lipid peroxide levels. The data established an essential role of GPx4 in protecting cells against lipid hydroperoxide damage, yet a limited role as a general antioxidant enzyme. As oxidized lipid hydroperoxides are a characteristic of neurodegenerative diseases, we analyzed brain tissues of mice suffering from a model of Alzheimer's disease and found that oxidized lipid by-products were enriched, and expression of both GPx4 and guanine-rich sequence-binding factor, which is known to control GPx4 synthesis, was downregulated. Brain tissue from an Alzheimer's diseased human also manifested enhanced levels of one of the oxidized lipid by-products, 4-hydroxynonenal. These data suggest a role of GPx4 in neurodegenerative diseases through its function in removal of lipid hydroperoxides.
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PMID:Delineating the role of glutathione peroxidase 4 in protecting cells against lipid hydroperoxide damage and in Alzheimer's disease. 1976 63

Reactive lipid hydroperoxides formed by lipoxygenases and cyclooxygenases can contribute to disease through cellular oxidative damage. Several selenoproteins have lipid hydroperoxidase activity, including glutathione peroxidase 4, thioredoxin reductase, and selenoprotein P (SelP). SelP is an extracellular glycoprotein that functions both in selenium distribution and has an antioxidant activity. The major objective of this study was to determine if an SelP, at physiological concentrations and in selenium replete media, possessed hydroperoxidase activity directed at lipid hydroperoxides generated from the metabolism of arachidonic acid by 15-lipoxygenase-1 (15-LOX-1). An SelP displayed in vitro lipid hydroperoxidase activity of 15-hydroperoxyeicosatetraenoic acid (15-HpETE), attenuated 15-HpETE oxidation in cellular assays, and in transcellular assay when 15-LOX-1 is metabolically active. These results suggest that an SelP can function as an antioxidant enzyme against reactive lipid intermediates formed during inflammation, but an SelP has modest activity. Nevertheless, this effect may help protect cells against the oxidative damage induced by these lipid metabolites.
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PMID:Selenoprotein P protects cells from lipid hydroperoxides generated by 15-LOX-1. 2082 80

Oxidative stress is implicated in the pathologies of photoreceptor cells, and the protective role of antioxidant enzymes for photoreceptor cells have been well understood. However, their essentiality has remained unknown. In this study we generated photoreceptor-specific conditional knock-out (CKO) mice of glutathione peroxidase 4 (GPx4) and showed the critical role of GPx4 for photoreceptor cells. In the wild-type retina the dominant GPx4 expression was in the mitochondria, indicating the mitochondrial variant was the major GPx4 in the retina. In the GPx4-CKO mice, although photoreceptor cells developed and differentiated into rod and cone cells by P12, they rapidly underwent drastic degeneration and completely disappeared by P21. The photoreceptor cell death in the GPx4-CKO mice was associated with the nuclear translocation of apoptosis-inducing factor (AIF) and TUNEL-positive cells. Photoreceptor cells before undergoing apoptosis (P11) exhibited decreased mitochondrial biomass, decreased number of connecting cilia, as well as disorganized structure of outer segments. These findings indicate that GPx4 is a critical antioxidant enzyme for the maturation and survival of photoreceptor cells.
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PMID:Glutathione peroxidase 4 is required for maturation of photoreceptor cells. 2220 60

The antioxidant enzyme glutathione peroxidase 4 (GPx4) is capable of reducing complex lipid hydroperoxides in addition to hydrogen peroxide and organic hydroperoxides. Mammals express three GPx4 isoforms that are targeted to nucleoli, mitochondria or cytosol via variable amino termini. To better understand the role of this important antioxidant enzyme in marine finfish, we determined the subcellular localisation of a GPx4 homologue from southern bluefin tuna (Thunnus maccoyii; SBT). We created constructs for the expression of the selenocysteine-to-cysteine mutant of SBT GPx4 (GPx4C) tagged with enhanced green fluorescent protein (EGFP), including or lacking a putative amino-terminal signal peptide, and expressed the fusion proteins in a fish cell line. Fluorescence microscopy revealed that the full-length GPx4C-EGFP fusion protein localised to the trans-Golgi, suggesting that tuna GPx4 may be directed to the secretory pathway. Anti-GFP immunoblotting of cell lysates and proteins from culture media showed that the secretion of SBT GPx4 into the culture medium required an amino-terminal signal peptide. According to available sequence data, the SBT GPx4 isoform studied here is representative of other piscine GPx4 isoforms, suggesting that the secretion of at least one GPx4 isoform may be common amongst teleost fish.
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PMID:A glutathione peroxidase 4 (GPx4) homologue from southern bluefin tuna is a secreted protein: first report of a secreted GPx4 isoform in vertebrates. 2228

Oxidative stress is involved in the pathophysiology of diabetic nephropathy. The superoxide-generating nicotinamide adenine dinucleotide phosphate-oxidase 2 (NOX2, encoded by the CYBB gene) and the antioxidant enzyme glutathione peroxidase 4 (GPX4) play opposing roles in the balance of cellular redox status. In the present study, we investigated associations of single nucleotide polymorphisms (SNPs) in the regulatory regions of CYBB and GPX4 with kidney disease in patients with type 1 diabetes. Two functional SNPs, rs6610650 (CYBB promoter region, chromosome X) and rs713041 (GPX4 3'untranslated region, chromosome 19), were genotyped in 451 patients with type 1 diabetes from a Brazilian cohort (diabetic nephropathy: 44.6%) and in 945 French/Belgian patients with type 1 diabetes from Genesis and GENEDIAB cohorts (diabetic nephropathy: 62.3%). The minor A-allele of CYBB rs6610650 was associated with lower estimated glomerular filtration rate (eGFR) in Brazilian women, and with the prevalence of established/advanced nephropathy in French/Belgian women (odds ratio 1.75, 95% CI 1.11-2.78, p = 0.016). The minor T-allele of GPX4 rs713041 was inversely associated with the prevalence of established/advanced nephropathy in Brazilian men (odds ratio 0.30, 95% CI 0.13-0.68, p = 0.004), and associated with higher eGFR in French/Belgian men. In conclusion, these heterogeneous results suggest that neither CYBB nor GPX4 are major genetic determinants of diabetic nephropathy, but nevertheless, they could modulate in a gender-specific manner the risk for renal disease in patients with type 1 diabetes.
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PMID:Sex-specific associations of variants in regulatory regions of NADPH oxidase-2 (CYBB) and glutathione peroxidase 4 (GPX4) genes with kidney disease in type 1 diabetes. 2391 99


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