Promoter Polymorphisms in the Plasma Glutathione Peroxidase (
            <i>GPx-3</i>
            ) Gene

Voetsch, Barbara; Jin, Richard C.; Bierl, Charlene; Benke, Kelly S.; Kenet, Gili; Simioni, Paolo; Ottaviano, Filomena G.; Damasceno, Benito Pereira; Annichino-Bizacchi, Joyce M.; Handy, Diane E.; Loscalzo, Joseph

doi:10.1161/01.str.0000252027.53766.2b

Cited by 124 publications

(61 citation statements)

References 38 publications

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“…Our group has previously shown no differences in placental GPx1, 3 and 4 mRNA expression between pregnancy groups [17]. However, the reduction of GPx activity and protein expression in the 275 preeclamptic placentae indicates a possible post-translational modification/mutation reducing the GPx antioxidant activity; this has been observed outside pregnancy [41].…”

Section: Significant 225mentioning

confidence: 60%

Differential expression and distribution of placental glutathione peroxidases 1, 3 and 4 in normal and preeclamptic pregnancy

et al. 2010

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A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. AbstractPreeclampsia is a pregnancy-specific condition affecting 2-7% of women and a leading cause of perinatal and maternal morbidity and mortality; it may also predispose the mother and fetus to increased risks of adult cardiovascular disease. The selenoprotein glutathione peroxidases (GPxs) have critical roles in regulating antioxidant status. 30Objectives, study design and main outcome measures: Immunohistochemical measurements of GPx 1, GPx3 and GPx4 protein expression were performed on samples taken from three standardised sampling sites between the cord insertion and the periphery of the placenta from 12 normotensive, and 12 preeclamptic women to establish if their expression differed between sampling sites. Total GPx activities were also examined from the 35 three sampling sites of these placentae.Results: There were highly significant reductions in overall immunohistochemical staining of all 3 GPxs in the preeclampsia compared to normotensive placentae (GPx1: P = 0.016; GPx3: P = 0.003; GPx4: P < 0.001). Furthermore, graded differences in expression between the standardised placental sampling sites were also found for GPx3 (higher in the inner region, P 40 = 0.05) and GPx4 (higher in the periphery, P = 0.02) but not GPx1. Placental GPx enzyme activity was also significantly reduced in tissue from preeclamptic women as compared to normotensive women (P = 0.007; the difference was more pronounced nearest the cord insertion). Conclusions:We have shown highly significant reductions in expression of all three major 45 classes of GPx in placentae from women with preeclampsia, and distribution gradients in activity, which may relate to the differential oxygenation of regions of the placenta.

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Section: Significant 225mentioning

confidence: 60%

Differential expression and distribution of placental glutathione peroxidases 1, 3 and 4 in normal and preeclamptic pregnancy

et al. 2010

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“…An SNP in the SELS promoter at position -105 is regarded as being functionally significant as it modulates levels of inflammatory markers such as TNF-a and interleukin (33) . Third, SNP have been identified in the promoter region of the GPX3 gene coding for the plasma glutathione peroxidase GPx3 and gene reporter experiments suggest that these affect promoter activity (36,37) .…”

Section: Functional Single-nucleotide Polymorphisms In Sels and Othermentioning

confidence: 99%

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar

Hesketh

Méplan

2011

Proc. Nutr. Soc.

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Micronutrients are essential for optimal human health. However, in some cases, raising intake by supplementation has not proven to be beneficial and there is even some evidence that supplementation may increase disease risk, highlighting the importance of assessing the functional status of micronutrients. Techniques such as gene microarrays and single-nucleotide polymorphism analysis have the potential to examine effects of micronutrient intake on patterns of gene expression and inter-individual variation in micronutrient metabolism. Recent genomic research related to selenium (Se) provides examples illustrating how studies of functional single-nucleotide polymorphism and gene expression patterns can reveal novel biomarkers of micronutrient function. Both in vitro and in vivo experiments show that there are functionally relevant polymorphisms in genes encoding glutathione peroxidases 1, 3 and 4, selenoprotein P, selenoprotein S and the 15 kDa selenoprotein. Disease association studies investigating these gene variants have so far been relatively small but an association of a polymorphism in the selenoprotein S gene with colorectal cancer risk has been replicated in two distinct populations. Future disease association studies should examine effects of multiple variants in combination with nutritional status. Gene microarray studies indicate that changes in Se intake alter expression of components of inflammatory, stress response and translation pathways. Our hypothesis is that Se intake and genetic factors have linked effects on stress response, inflammation and apoptotic pathways. Combining such data in a systems biology approach has the potential to identify both biomarkers of micronutrients status and sub-group populations at particular risk.

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“…The less common haplotype (H2) had reduced GPx-3 transcriptional activity in a reporter gene assay, and was significantly more prevalent among stroke patients than controls, suggesting a link between the GPx-3 promoter polymorphisms and the risk for arterial ischemic stroke in the young. 239 GPx-3 has been proposed as a major scavenger of ROS in plasma, thus maintaining NO bioavailability and an antithrombotic environment in the vasculature. 240 Its deficiency may lead to platelet activation and a prothrombotic state and predispose to arterial thrombotic disease.…”

Section: Plasma Gsh Peroxidase (Gpx-3)mentioning

confidence: 99%

Redox Regulation in the Extracellular Environment

Ottaviano

Handy

Loscalzo

2008

Circ J

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120

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Molecular oxygen is involved in the oxidation of substrates used to produce energy; however, normal metabolism can also generate harmful (bio)chemical byproducts. These deleterious products are partially reduced forms of oxygen, and include free radicals such as superoxide anion radical, hydroxyl radical, or highly oxidizing non-radical species such as hydrogen peroxide (H2O2) and lipid peroxides, which are collectively known as ROS. 1 ROS typically derive from normal metabolism, activated leukocytes, and ambient oxygen in the environment. The production and accumulation of ROS and their downstream effects can be controlled or attenuated by antioxidants. When the ability of antioxidants to eliminate harmful cellular and extracellular ROS is compromised, the balance between ROS generation and antioxidant function to eliminate ROS is shifted in favor of an accumulation of oxidants, which defines the state of oxidative stress in a cell or organism. Oxidative damage can affect DNA, lipids, and proteins, and eventually compromise cell integrity. Many studies have implicated ROS in the pathological processes leading to heart disease, cancer, aging, AIDS, and inflammatory and autoimmune diseases.Oxidants, especially free radicals, are highly reactive. Superoxide can react within milliseconds with nitric oxide (NO) to produce peroxynitrite (ONOO -), a reactive nitrogen species (RNS). The nitrosium cation and nitroxyl anion are other RNS derived from NO. 2 Peroxynitrite is a strong oxidant involved in the nitrosative modification of proteins and lipids. Owing to its rapid reaction with NO, superoxide may modulate NO bioavailability and, subsequently, regulate vascular function. 3 Circulation Journal Vol.72, January 2008The cytosol, mitochondria, peroxisomes, and plasma are all potential sites of ROS formation. 4 The major sources of ROS are enzymatic via nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (Nox), xanthine oxidase, myeloperoxidase, endothelial NO synthase (eNOS), or as a consequence of normal mitochondrial respiration. In vascular cells, other enzymatic sources of ROS include cytochrome P450 isoenzymes, lipoxygenase, cyclooxygenase, heme oxygenase, and glucose oxidase. 1,3,[5][6][7] Most reviews to date have focused on the role of intracellular antioxidants that eliminate ROS from the intracellular environment. There are, however, several extracellular antioxidants that also play an equally important role in limiting ROS accumulation in the extracellular environment. Along with limiting ROS accumulation, extracellular redox status is essential for maintaining protein stability and function.The major enzymes important for the elimination of extracellular H2O2 are glutathione peroxidase-3 (GPx-3) and peroxiredoxin IV (Prx IV). Other extracellular antioxidants involved in ROS elimination include paraoxonase (PON), thioredoxin (Trx), Trx reductase (TrxR), glutaredoxin (Grx), extracellular superoxide dismutase (EC-SOD), and extracellular glutathione (GSH).Some of these antioxidants, notably glutathione...

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Promoter Polymorphisms in the Plasma Glutathione Peroxidase ( GPx-3 ) Gene

Cited by 124 publications

References 38 publications

Differential expression and distribution of placental glutathione peroxidases 1, 3 and 4 in normal and preeclamptic pregnancy

Differential expression and distribution of placental glutathione peroxidases 1, 3 and 4 in normal and preeclamptic pregnancy

Transcriptomics and functional genetic polymorphisms as biomarkers of micronutrient function: focus on selenium as an exemplar

Redox Regulation in the Extracellular Environment

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