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Peter J Crack - One of the best experts on this subject based on the ideXlab platform.
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Glutathione Peroxidase-1 Contributes to the Neuroprotection Seen in the Superoxide Dismutase-1 Transgenic Mouse in Response to Ischemia/Reperfusion Injury:
Journal of Cerebral Blood Flow and Metabolism, 2020Co-Authors: Peter J Crack, Judy B De Haan, Paul J Hertzog, Ismail Kola, Juliet M Taylor, Rocco C. IannelloAbstract:The authors hypothesized that Glutathione Peroxidase-1 (Gpx-1) contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic (Sod-1 tg) mouse. To investigate this hypothesis, they crossed the Gpx-1 -/- mouse with the Sod-1 tg and subjected the cross to a mouse model of ischemia/reperfusion. Two hours of focal cerebral ischemia followed by 24 hours of reperfusion was induced via intraluminal suture. The Sod-1 tg/Gpx-1 -/- cross exhibited no neuroprotection when infarct volume was measured; indeed, infarct volume increased in the Sod-1 tg/Gpx-1 -/- cross compared with the wild-type mouse. Our results suggest that Gpx-1 plays an important regulatory role in the protection of neural cells in response to ischemia/reperfusion injury.
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Glutathione Peroxidase 1 primes pro inflammatory cytokine production after lps challenge in vivo
PLOS ONE, 2012Co-Authors: Steven Bozinovski, Huei Jiunn Seow, Peter J Crack, Gary P Anderson, Ross VlahosAbstract:Reactive oxygen species produced during the innate immune response to LPS are important agents of anti-pathogen defence but may also cause oxidative lung damage. Glutathione Peroxidase-1 (gpx-1) is an anti-oxidant enzyme that may protect lungs from such damage. We assessed the in vivo importance of gpx-1 in LPS-induced lung inflammation. Male wild-type (WT) or gpx-1 deficient (gpx-1−/−) mice were treated intranasally with PBS or 10 µg LPS and killed 3 and 24 h post LPS. Lungs were lavaged with PBS and then harvested for inflammatory marker expression. LPS caused an intense neutrophilia in WT BALF evident 3 and 24 h post challenge that was reduced in gpx-1−/− mice. In addition, LPS-treated gpx-1−/− mice had significantly fewer macrophages than LPS-treated WT mice. To understand the basis for this paradoxical reduction we assessed inflammatory cytokines and proteases at protein and transcript levels. MMP-9 expression and net gelatinase activity in BALF of gpx-1−/− mice treated with LPS for 3 and 24 h was no different to that found in LPS-treated WT mice. BALF from LPS-treated gpx-1−/− mice (3 h) had less TNF-α, MIP-2 and GM-CSF protein than LPS-treated WT mice. In contrast, LPS-induced increases in TNF-α, MIP-2 and GM-CSF mRNA expression in WT mice were similar to those observed in gpx-1−/− mice. These attenuated protein levels were unexpectedly not mirrored by reduced mRNA transcripts but were associated with increased 20S proteasome expression. Thus, these data suggest that gpx-1 primes pro-inflammatory cytokine production after LPS challenge in vivo.
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Glutathione Peroxidase-1 as a therapeutic target in influenza A virus-induced lung disease
European Respiratory Journal, 2011Co-Authors: Selcuk Yatmaz, Huei Jiunn Seow, Steven Bozinovski, Peter J Crack, Gary P Anderson, Rosa C. Gualano, Zi Xin Wong, Ross VlahosAbstract:Introduction: Oxidative stress and reactive oxygen species (ROS) are implicated in influenza A virus-induced lung inflammation and damage. Current therapies primarily target viral infection and replication, with little attention directed at the host immune response. The antioxidant enzyme Glutathione Peroxidase-1 (GPx-1) has a protective role against various diseases involving ROS. Aim: To study the role of GPx-1 in influenza A virus-induced lung inflammation. Methods: Male WT (C57BL/6) and GPx-1-/-mice were infected with 1×104 PFU of HKx31 (H3N2) influenza A virus. Viral titre, BALF and lung inflammation, body weight, pro-inflammatory chemokine (MIP-1α, MIP-2, KC) and protease (MMP-9) expression were assessed 3 and 7 days post infection. Results: WT mice infected with HKx31 had significantly more BALF total cells, macrophages, neutrophils and lymphocytes at day 3 and 7 than naive WT animals (n=5-8, P
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A global transcriptomic view of the multifaceted role of Glutathione Peroxidase-1 in cerebral ischemic-reperfusion injury
Free Radical Biology and Medicine, 2010Co-Authors: Minghui Jessica Chen, Peter J Crack, Connie H. Y. Wong, Zhao Feng Peng, Jayapal Manikandan, Alirio J. Melendez, Nam Sang CheungAbstract:Abstract Transient cerebral ischemia often results in secondary ischemic/reperfusion injury, the pathogenesis of which remains unclear. This study provides a comprehensive, temporal description of the molecular events contributing to neuronal injury after transient cerebral ischemia. Intraluminal middle cerebral artery occlusion (MCAO) was performed to induce a 2-h ischemia with reperfusion. Microarray analysis was then performed on the infarct cortex of wild-type (WT) and Glutathione Peroxidase-1 (a major antioxidant enzyme) knockout (Gpx1−/−) mice at 8 and 24 h postreperfusion to identify differential gene expression profile patterns and potential alternative injury cascades in the absence of Gpx1, a crucial antioxidant enzyme, in cerebral ischemia. Genes with at least ± 1.5-fold change in expression at either time point were considered significant. Global transcriptomic analyses demonstrated that 70% of the WT-MCAO profile overlapped with that of Gpx1−/−-MCAO, and 28% vice versa. Critical analysis of the 1034 gene probes specific to the Gpx1−/−-MCAO profile revealed regulation of additional novel pathways, including the p53-mediated proapoptotic pathway and Fas ligand (CD95/Apo1)-mediated pathways; downplay of the Nrf2 antioxidative cascade; and ubiquitin–proteasome system dysfunction. Therefore, this comparative study forms the foundation for the establishment of screening platforms for target definition in acute cerebral ischemia intervention.
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Glutathione Peroxidase 1 protects against cigarette smoke induced lung inflammation in mice
American Journal of Physiology-lung Cellular and Molecular Physiology, 2010Co-Authors: Chi Duong, Huei Jiunn Seow, Steven Bozinovski, Peter J Crack, Gary P Anderson, Ross VlahosAbstract:Reactive oxygen species (ROS) produced from cigarette smoke cause oxidative lung damage including protein denaturation, lipid peroxidation, and DNA damage. Glutathione Peroxidase-1 (gpx-1) is a det...
Ismail Kola - One of the best experts on this subject based on the ideXlab platform.
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Glutathione Peroxidase-1 Contributes to the Neuroprotection Seen in the Superoxide Dismutase-1 Transgenic Mouse in Response to Ischemia/Reperfusion Injury:
Journal of Cerebral Blood Flow and Metabolism, 2020Co-Authors: Peter J Crack, Judy B De Haan, Paul J Hertzog, Ismail Kola, Juliet M Taylor, Rocco C. IannelloAbstract:The authors hypothesized that Glutathione Peroxidase-1 (Gpx-1) contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic (Sod-1 tg) mouse. To investigate this hypothesis, they crossed the Gpx-1 -/- mouse with the Sod-1 tg and subjected the cross to a mouse model of ischemia/reperfusion. Two hours of focal cerebral ischemia followed by 24 hours of reperfusion was induced via intraluminal suture. The Sod-1 tg/Gpx-1 -/- cross exhibited no neuroprotection when infarct volume was measured; indeed, infarct volume increased in the Sod-1 tg/Gpx-1 -/- cross compared with the wild-type mouse. Our results suggest that Gpx-1 plays an important regulatory role in the protection of neural cells in response to ischemia/reperfusion injury.
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lack of the antioxidant enzyme Glutathione Peroxidase 1 accelerates atherosclerosis in diabetic apolipoprotein e deficient mice
Circulation, 2007Co-Authors: Paul Lewis, Nada Stefanovic, Ismail Kola, Josefa Pete, Anna C Calkin, S Giunti, Vicki Thallasbonke, Karin Jandeleitdahm, Terri J AllenAbstract:Background— Recent clinical studies have suggested a major protective role for the antioxidant enzyme Glutathione Peroxidase-1 (GPx1) in diabetes-associated atherosclerosis. We induced diabetes in mice deficient for both GPx1 and apolipoprotein E (ApoE) to determine whether this is merely an association or whether GPx1 has a direct effect on diabetes-associated atherosclerosis. Methods and Results— ApoE-deficient (ApoE−/−) and ApoE/GPx1 double-knockout (ApoE−/−GPx1−/−) mice were made diabetic with streptozotocin and aortic lesion formation, and atherogenic pathways were assessed after 10 and 20 weeks of diabetes. Aortic proinflammatory and profibrotic markers were determined by both quantitative reverse-transcription polymerase chain reaction analysis after 10 weeks of diabetes and immunohistochemical analysis after 10 and 20 weeks of diabetes. Sham-injected nondiabetic counterparts served as controls. Atherosclerotic lesions within the aortic sinus region, as well as arch, thoracic, and abdominal lesions...
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Lack of the Antioxidant Enzyme Glutathione Peroxidase-1 Accelerates Atherosclerosis in Diabetic Apolipoprotein E–Deficient Mice
Circulation, 2007Co-Authors: Paul C Lewis, Nada Stefanovic, Ismail Kola, Josefa Pete, Anna C Calkin, S Giunti, Terri J Allen, Vicki Thallas-bonke, Karin Jandeleit-dahm, Mark E. CooperAbstract:Background— Recent clinical studies have suggested a major protective role for the antioxidant enzyme Glutathione Peroxidase-1 (GPx1) in diabetes-associated atherosclerosis. We induced diabetes in mice deficient for both GPx1 and apolipoprotein E (ApoE) to determine whether this is merely an association or whether GPx1 has a direct effect on diabetes-associated atherosclerosis. Methods and Results— ApoE-deficient (ApoE−/−) and ApoE/GPx1 double-knockout (ApoE−/−GPx1−/−) mice were made diabetic with streptozotocin and aortic lesion formation, and atherogenic pathways were assessed after 10 and 20 weeks of diabetes. Aortic proinflammatory and profibrotic markers were determined by both quantitative reverse-transcription polymerase chain reaction analysis after 10 weeks of diabetes and immunohistochemical analysis after 10 and 20 weeks of diabetes. Sham-injected nondiabetic counterparts served as controls. Atherosclerotic lesions within the aortic sinus region, as well as arch, thoracic, and abdominal lesions...
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Retinal Light Damage: Structural and Functional Effects of the Antioxidant Glutathione Peroxidase-1
Investigative Ophthalmology & Visual Science, 2006Co-Authors: Andrew D. Gosbell, Nada Stefanovic, Lyndee L Scurr, Ismail Kola, Josefa Pete, Ian Favilla, Judy B De HaanAbstract:PURPOSE. The role of the antioxidant enzyme Glutathione Peroxidase-1 (GPx1) in protecting the retina against photo-oxidative damage was investigated in GPxl-deficient and wild-type mice. METHOD. Albino GPxl-deficient and age-matched wild-type mice were examined. Baseline electroretinograms (ERGs) were recorded. Thereafter, mice were exposed to intense light for 12 hours. After a 24-hour recovery in darkness, post-light-insult ERGs were recorded and compared with baseline. Structural effects of light insult were evaluated by retinal histology. Antioxidant expression was investigated by quantitative reverse transcription-PCR (qRT-PCR). RESULTS. light insult significantly affected ERG responses, with reduced a- and b-wave amplitudes. Structurally, photoreceptor layers were predominantly affected. As expected, GPxl expression was negligible in GPx1-deficient mice but was upregulated in wild-type mice in response to light insult. Similarly, hemeoxygenase-1 and thioredoxin-1 expression increased significantly in wild-type retinas after light exposure. Catalase, GPx isoforms (GPx2 to -4), peroxiredoxin-6, glutaredoxin-1, and thioredoxin-2 expression was unaffected by GPx1 deficiency and light insult, whereas significant increases in glutaredoxin-2 occurred in non-light-exposed (baseline) GPxl-deficient retinas. Compared with baseline wild-type retinas, lipid peroxidation (TBARS assay), an indicator of oxidative stress, was elevated in baseline GPx1-deficient retinas. Unexpectedly, the light insult induced diminution of retinal function, in terms of ERG amplitude, and structural damage was significantly greater in wild-type than in with GPx1-deficient retinas. CONCLUSIONS. The data showing increased oxidative damage in baseline GPx-deficient retina give rise to the hypothesis that increased oxidative stress provides a "preconditioning" environment in which protective mechanisms paradoxically render GPxl-deficient retinas less vulnerable to light-induced oxidative damage. This study identified glutaredoxin-2 as a potential candidate.
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kidney expression of Glutathione Peroxidase 1 is not protective against streptozotocin induced diabetic nephropathy
American Journal of Physiology-renal Physiology, 2005Co-Authors: Judy B De Haan, Nada Stefanovic, David J Nikolicpaterson, Lyndee L Scurr, Kevin D Croft, Trevor A Mori, Paul J Hertzog, Ismail Kola, Robert C Atkins, Gregory H TeschAbstract:In many diseases, including progressive renal disorders, tissue injury and pathological intracellular signaling events are dependent on oxidative stress. Glutathione Peroxidase-1 (Gpx1) is an antio...
Michael Torzewski - One of the best experts on this subject based on the ideXlab platform.
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Glutathione Peroxidase 1 deficiency potentiates dysregulatory modifications of endothelial nitric oxide synthase and vascular dysfunction in aging
Hypertension, 2014Co-Authors: Matthias Oelze, Huige Li, Edith Lubos, Swenja Krollerschon, Sebastian Steven, Christopher Doppler, Michael Hausding, Silke Tobias, Christoph Brochhausen, Michael TorzewskiAbstract:Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in Glutathione Peroxidase-1–deficient ( GPx-1 −/− ) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1 −/− mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1 −/− -mice as compared with age-matched controls. Oxidant formation, detected by 3-nitrotyrosine staining and dihydroethidine-based fluorescence microtopography, was increased in the aged GPx-1 −/− mice. Aging per se caused a substantial protein kinase C– and protein tyrosine kinase–dependent phosphorylation as well as S-glutathionylation of endothelial NO synthase associated with uncoupling, a phenomenon that was more pronounced in aged GPx-1 −/− mice. GPx-1 ablation increased adhesion of leukocytes to cultured endothelial cells and CD68 and F4/80 staining in cardiac tissue. Aged GPx-1 −/− mice displayed increased oxidant formation as compared with their wild-type littermates, triggering redox-signaling pathways associated with endothelial NO synthase dysfunction and uncoupling. Thus, our data demonstrate that aging leads to decreased NO bioavailability because of endothelial NO synthase dysfunction and uncoupling of the enzyme leading to endothelial dysfunction, vascular remodeling, and promotion of adhesion and infiltration of leukocytes into cardiovascular tissue, all of which was more prominent in aged GPx-1 −/− mice.
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deficiency of Glutathione Peroxidase 1 accelerates the progression of atherosclerosis in apolipoprotein e deficient mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Michael Torzewski, Viola Ochsenhirt, Andrei L Kleschyov, Matthias Oelze, Andreas Daiber, Huige Li, Heidi Rossmann, Sotirios Tsimikas, Kurt Reifenberg, Fei ChengAbstract:Background— We have recently demonstrated that activity of red blood cell Glutathione Peroxidase-1 is inversely associated with the risk of cardiovascular events in patients with coronary artery disease. The present study analyzed the effect of Glutathione Peroxidase-1 deficiency on atherogenesis in the apolipoprotein E-deficient mouse. Methods and Results— Female apolipoprotein E-deficient mice with and without Glutathione Peroxidase-1 deficiency were placed on a Western-type diet for another 6, 12, or 24 weeks. After 24 weeks on Western-type diet, double-knockout mice (GPx-1−/−ApoE−/−) developed significantly more atherosclerosis than control apolipoprotein E-deficient mice. Moreover, Glutathione Peroxidase-1 deficiency led to modified atherosclerotic lesions with increased cellularity. Functional experiments revealed that Glutathione Peroxidase-1 deficiency leads to increased reactive oxygen species concentration in the aortic wall as well as increased overall oxidative stress. Peritoneal macrophages from double-knockout mice showed increased in vitro proliferation in response to macrophage-colony-stimulating factor. Also, we found lower levels of bioactive nitric oxide as well as increased tyrosine nitration as a marker of peroxynitrite production. Conclusions— Deficiency of an antioxidative enzyme accelerates and modifies atherosclerotic lesion progression in apolipoprotein E-deficient mice.
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Glutathione Peroxidase 1 activity and cardiovascular events in patients with coronary artery disease
Obstetrical & Gynecological Survey, 2004Co-Authors: Stefan Blankenberg, Hans J. Rupprecht, Christoph Bickel, Michael Torzewski, Gerd Hafner, Laurence Tiret, Marek Smieja, François Cambien, J Rgen Meyer, Karl J. LacknerAbstract:Along with superoxide dismutase, Glutathione Peroxidase 1 is one of the cellular antioxidant enzymes that have a key role in controlling reactive oxygen species. It uses Glutathione to reduce hydrogen peroxide to water and lipid peroxides to their respective alcohols. There are suggestions from in vitro and animal studies that these enzymes could protect against atherosclerosis. This prospective study examined the possibility that relatively high activity of antioxidant enzymes protects against cardiovascular events. The study population included 636 patients suspected of having coronary artery disease who were followed for a median period of 4.7 years. Stable angina was present in 510 patients and symptoms of unstable angina in 133. Coronary angiography disclosed coronary artery disease with more than 30% stenosis of at least 1 major coronary artery in 558 patients. Enzyme activities were measured in washed red blood cells. Baseline levels of Glutathione Peroxidase 1 activity were significantly lower in patients who died of cardiac causes or had a nonfatal myocardial infarction than in those not having either of these events. The relationship persisted when patients who died and those with nonfatal events were separately analyzed. Rates of cardiovascular events increased across decreasing quartiles of baseline enzyme activity; patients in the lowest quartile had approximately 3 times more events than those in the highest quartile. Enzyme activity was lower in current smokers than in those who had never smoked. Except for statins, which were associated with higher Glutathione Peroxidase 1 activity, there was no apparent association between cardiovascular medications and the activity of either Glutathione Peroxidase 1 or superoxide dismutase. The inverse relationship between Glutathione Peroxidase 1 activity and the relative risk of coronary disease events was changed very little after adjusting for cardiovascular risk factors and clinical features. Patients with the highest Glutathione Peroxidase 1 activity had a hazard ratio of 0.29 (95% confidence interval, 0.14-0.60) compared with those in the lowest quartile. These findings indicate that in patients with coronary artery disease, red blood cell levels of Glutathione Peroxidase 1 activity are inversely associated with the risk of future cardiovascular events, both fatal and nonfatal. Estimating enzyme activity might prove helpful for identifying patients who would benefit from prophylactic antioxidant treatment.
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Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients with Coronary Artery Disease
The New England Journal of Medicine, 2003Co-Authors: Stefan Blankenberg, Hans J. Rupprecht, Christoph Bickel, Michael Torzewski, Gerd Hafner, Laurence Tiret, Marek Smieja, François Cambien, Jürgen Meyer, Karl J. LacknerAbstract:Background Cellular antioxidant enzymes such as Glutathione Peroxidase 1 and superoxide dismutase have a central role in the control of reactive oxygen species. In vitro data and studies in animal models suggest that these enzymes may protect against atherosclerosis, but little is known about their relevance to human disease. Methods We conducted a prospective study among 636 patients with suspected coronary artery disease, with a median follow-up period of 4.7 years (maximum, 5.4) to assess the risk of cardiovascular events associated with base-line erythrocyte Glutathione Peroxidase 1 and superoxide dismutase activity. Results Glutathione Peroxidase 1 activity was among the strongest univariate predictors of the risk of cardiovascular events, whereas superoxide dismutase activity had no association with risk. The risk of cardiovascular events was inversely associated with increasing quartiles of Glutathione Peroxidase 1 activity (P for trend
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Glutathione Peroxidase 1 activity and cardiovascular events in patients with coronary artery disease
The New England Journal of Medicine, 2003Co-Authors: Stefan Blankenberg, Hans J. Rupprecht, Christoph Bickel, Michael Torzewski, Gerd Hafner, Laurence Tiret, Marek Smieja, François Cambien, Jürgen Meyer, Karl J. LacknerAbstract:Background Cellular antioxidant enzymes such as Glutathione Peroxidase 1 and superoxide dismutase have a central role in the control of reactive oxygen species. In vitro data and studies in animal models suggest that these enzymes may protect against atherosclerosis, but little is known about their relevance to human disease. Methods We conducted a prospective study among 636 patients with suspected coronary artery disease, with a median follow-up period of 4.7 years (maximum, 5.4) to assess the risk of cardiovascular events associated with base-line erythrocyte Glutathione Peroxidase 1 and superoxide dismutase activity. Results Glutathione Peroxidase 1 activity was among the strongest univariate predictors of the risk of cardiovascular events, whereas superoxide dismutase activity had no association with risk. The risk of cardiovascular events was inversely associated with increasing quartiles of Glutathione Peroxidase 1 activity (P for trend <0.001); patients in the highest quartile of Glutathione perox...
Stefan Blankenberg - One of the best experts on this subject based on the ideXlab platform.
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Inflammatory bowel disease (IBD) locus 12: is Glutathione Peroxidase-1 (GPX1) the relevant gene?
Genes and Immunity, 2015Co-Authors: Friederike Häuser, Stefan Blankenberg, Heidi Rossmann, Dagmar Laubert-reh, Philipp S. Wild, Tanja Zeller, Christian P. Müller, Neuwirth S, Karl J. LacknerAbstract:Inflammatory bowel disease (IBD) locus 12: is Glutathione Peroxidase-1 ( GPX1 ) the relevant gene?
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Glutathione Peroxidase 1 activity atherosclerotic burden and cardiovascular prognosis
American Journal of Cardiology, 2007Co-Authors: Christine Espinolaklein, Hans J. Rupprecht, Christoph Bickel, Karl J. Lackner, Renate B. Schnabel, Micheal Torzewski, Thomas Münzel, Sabine Genthzotz, Stefan BlankenbergAbstract:Recent findings suggest that erythrocyte intracellular Glutathione Peroxidase-1 (GPX-1) activity is related inversely to future cardiovascular events. The aim of this study is to evaluate the association of GPX-1 activity to extent of atherosclerosis, as well as its long-term prognosis in context with atherosclerotic burden. In a prospective study, we included 508 patients before coronary angiography. Atherosclerosis of carotid and leg arteries was documented using sonographic methods. Blood samples were drawn after an overnight fasting period, and GPX-1 activity was determined in washed erythrocytes. GPX-1 activity tended to decrease with increasing numbers of atherosclerotic vascular beds, so that patients without clinically relevant atherosclerosis had GPX-1 activity of 49.3 U/g hemoglobin compared with 46.0 U/g hemoglobin in patients with prevalent atherosclerosis in all 3 vascular beds (p = NS). Follow-up data (median 6.5 years) were available for 504 patients (99.2%), and 96 patients (19.0%) experienced cardiovascular events (cardiovascular death, infarction, and stroke). The event rate was inversely associated with level of GPX-1 activity divided into tertiles (hazard ratio 2.3, 95% confidence interval 1.4 to 4.0 for lowest vs highest tertile of GPX-1 activity, p = 0.002, adjusted). The highest event rate was found in persons with low GPX-1 activity and multivascular atherosclerosis (event rate 36.9%, p <0.0001). In conclusion, decreased red blood cell GPX-1 activity is associated with increased cardiovascular risk according to the extent of atherosclerosis.
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Glutathione Peroxidase-1 Activity, Atherosclerotic Burden, and Cardiovascular Prognosis
American Journal of Cardiology, 2007Co-Authors: Christine Espinola-klein, Hans J. Rupprecht, Christoph Bickel, Karl J. Lackner, Renate B. Schnabel, Sabine Genth-zotz, Micheal Torzewski, Thomas Münzel, Stefan BlankenbergAbstract:Recent findings suggest that erythrocyte intracellular Glutathione Peroxidase-1 (GPX-1) activity is related inversely to future cardiovascular events. The aim of this study is to evaluate the association of GPX-1 activity to extent of atherosclerosis, as well as its long-term prognosis in context with atherosclerotic burden. In a prospective study, we included 508 patients before coronary angiography. Atherosclerosis of carotid and leg arteries was documented using sonographic methods. Blood samples were drawn after an overnight fasting period, and GPX-1 activity was determined in washed erythrocytes. GPX-1 activity tended to decrease with increasing numbers of atherosclerotic vascular beds, so that patients without clinically relevant atherosclerosis had GPX-1 activity of 49.3 U/g hemoglobin compared with 46.0 U/g hemoglobin in patients with prevalent atherosclerosis in all 3 vascular beds (p = NS). Follow-up data (median 6.5 years) were available for 504 patients (99.2%), and 96 patients (19.0%) experienced cardiovascular events (cardiovascular death, infarction, and stroke). The event rate was inversely associated with level of GPX-1 activity divided into tertiles (hazard ratio 2.3, 95% confidence interval 1.4 to 4.0 for lowest vs highest tertile of GPX-1 activity, p = 0.002, adjusted). The highest event rate was found in persons with low GPX-1 activity and multivascular atherosclerosis (event rate 36.9%, p
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Glutathione Peroxidase 1 activity and cardiovascular events in patients with coronary artery disease
Obstetrical & Gynecological Survey, 2004Co-Authors: Stefan Blankenberg, Hans J. Rupprecht, Christoph Bickel, Michael Torzewski, Gerd Hafner, Laurence Tiret, Marek Smieja, François Cambien, J Rgen Meyer, Karl J. LacknerAbstract:Along with superoxide dismutase, Glutathione Peroxidase 1 is one of the cellular antioxidant enzymes that have a key role in controlling reactive oxygen species. It uses Glutathione to reduce hydrogen peroxide to water and lipid peroxides to their respective alcohols. There are suggestions from in vitro and animal studies that these enzymes could protect against atherosclerosis. This prospective study examined the possibility that relatively high activity of antioxidant enzymes protects against cardiovascular events. The study population included 636 patients suspected of having coronary artery disease who were followed for a median period of 4.7 years. Stable angina was present in 510 patients and symptoms of unstable angina in 133. Coronary angiography disclosed coronary artery disease with more than 30% stenosis of at least 1 major coronary artery in 558 patients. Enzyme activities were measured in washed red blood cells. Baseline levels of Glutathione Peroxidase 1 activity were significantly lower in patients who died of cardiac causes or had a nonfatal myocardial infarction than in those not having either of these events. The relationship persisted when patients who died and those with nonfatal events were separately analyzed. Rates of cardiovascular events increased across decreasing quartiles of baseline enzyme activity; patients in the lowest quartile had approximately 3 times more events than those in the highest quartile. Enzyme activity was lower in current smokers than in those who had never smoked. Except for statins, which were associated with higher Glutathione Peroxidase 1 activity, there was no apparent association between cardiovascular medications and the activity of either Glutathione Peroxidase 1 or superoxide dismutase. The inverse relationship between Glutathione Peroxidase 1 activity and the relative risk of coronary disease events was changed very little after adjusting for cardiovascular risk factors and clinical features. Patients with the highest Glutathione Peroxidase 1 activity had a hazard ratio of 0.29 (95% confidence interval, 0.14-0.60) compared with those in the lowest quartile. These findings indicate that in patients with coronary artery disease, red blood cell levels of Glutathione Peroxidase 1 activity are inversely associated with the risk of future cardiovascular events, both fatal and nonfatal. Estimating enzyme activity might prove helpful for identifying patients who would benefit from prophylactic antioxidant treatment.
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Glutathione Peroxidase 1 Activity and Cardiovascular Events in Patients with Coronary Artery Disease
The New England Journal of Medicine, 2003Co-Authors: Stefan Blankenberg, Hans J. Rupprecht, Christoph Bickel, Michael Torzewski, Gerd Hafner, Laurence Tiret, Marek Smieja, François Cambien, Jürgen Meyer, Karl J. LacknerAbstract:Background Cellular antioxidant enzymes such as Glutathione Peroxidase 1 and superoxide dismutase have a central role in the control of reactive oxygen species. In vitro data and studies in animal models suggest that these enzymes may protect against atherosclerosis, but little is known about their relevance to human disease. Methods We conducted a prospective study among 636 patients with suspected coronary artery disease, with a median follow-up period of 4.7 years (maximum, 5.4) to assess the risk of cardiovascular events associated with base-line erythrocyte Glutathione Peroxidase 1 and superoxide dismutase activity. Results Glutathione Peroxidase 1 activity was among the strongest univariate predictors of the risk of cardiovascular events, whereas superoxide dismutase activity had no association with risk. The risk of cardiovascular events was inversely associated with increasing quartiles of Glutathione Peroxidase 1 activity (P for trend
Judy B De Haan - One of the best experts on this subject based on the ideXlab platform.
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Glutathione Peroxidase-1 Contributes to the Neuroprotection Seen in the Superoxide Dismutase-1 Transgenic Mouse in Response to Ischemia/Reperfusion Injury:
Journal of Cerebral Blood Flow and Metabolism, 2020Co-Authors: Peter J Crack, Judy B De Haan, Paul J Hertzog, Ismail Kola, Juliet M Taylor, Rocco C. IannelloAbstract:The authors hypothesized that Glutathione Peroxidase-1 (Gpx-1) contributes to the neuroprotection seen in the superoxide dismutase-1 transgenic (Sod-1 tg) mouse. To investigate this hypothesis, they crossed the Gpx-1 -/- mouse with the Sod-1 tg and subjected the cross to a mouse model of ischemia/reperfusion. Two hours of focal cerebral ischemia followed by 24 hours of reperfusion was induced via intraluminal suture. The Sod-1 tg/Gpx-1 -/- cross exhibited no neuroprotection when infarct volume was measured; indeed, infarct volume increased in the Sod-1 tg/Gpx-1 -/- cross compared with the wild-type mouse. Our results suggest that Gpx-1 plays an important regulatory role in the protection of neural cells in response to ischemia/reperfusion injury.
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Does lack of Glutathione Peroxidase 1 gene expression exacerbate lung injury induced by neonatal hyperoxia in mice
American Journal of Physiology-lung Cellular and Molecular Physiology, 2017Co-Authors: Sheena Bouch, Judy B De Haan, Megan O’reilly, Richard Harding, Foula SozoAbstract:Supplemental oxygen (O2) increases the risk of lung injury in preterm infants, owing to an immature antioxidant system. Our objective was to determine whether impairing antioxidant defense by decreasing Glutathione Peroxidase 1 (GPx1) gene expression increases the injurious effects of hyperoxia (Hyp). GPx1+/+ and GPx1−/− C57Bl/6J mice were exposed to 21% O2 (Air) or 40% O2 (Hyp) from birth to postnatal day 7 (P7d); they were euthanized on P7d or maintained in air until adulthood [postnatal day 56 (P56d)] to assess short-term and long-term effects, respectively. We assessed lung architecture, three markers of pulmonary oxidative stress (P7d, P56d), macrophages in lung tissue (P7d), immune cells in bronchoalveolar lavage fluid (BALF; P56d), and GPx1-4 and catalase gene expression in lung tissue (P7d, P56d). On P7d, macrophages were decreased by lack of GPx1 expression and further decreased by hyperoxia. GPx1 expression was increased in GPx1+/+Hyp mice and decreased in both GPx1−/− groups. On P56d, heme oxyg...
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lack of Glutathione Peroxidase 1 facilitates a pro inflammatory and activated vascular endothelium
Vascular Pharmacology, 2016Co-Authors: Arpeeta Sharma, Nada Stefanovic, Derek Y C Yuen, Olivier Huet, Raelene Pickering, Pascal Bernatchez, Judy B De HaanAbstract:A critical early event in the pathogenesis of atherosclerosis is vascular inflammation leading to endothelial dysfunction (ED). Reactive oxygen species and inflammation are inextricably linked and declining antioxidant defense is implicated in ED. We have previously shown that Glutathione Peroxidase-1 (GPx1) is a crucial antioxidant enzyme in the protection against diabetes-associated atherosclerosis. In this study we aimed to investigate mechanisms by which lack of GPx1 affects pro-inflammatory mediators in primary aortic endothelial cells (PAECs) isolated from GPx1 knockout (GPx1 KO) mice. Herein, we demonstrate that lack of GPx1 prolonged TNF-α induced phosphorylation of P38, ERK and JNK, all of which was reversed upon treatment with the GPx1 mimetic, ebselen. In addition, Akt phosphorylation was reduced in GPx1 KO PAECs, which correlated with decreased nitric oxide (NO) bioavailability as compared to WT PAECs. Furthermore, IκB degradation was prolonged in GPx1 KO PAECS suggesting an augmentation of NF-κB activity. In addition, the expression of vascular cell adhesion molecule (VCAM-1) was significantly increased in GPx1 KO PAECs and aortas. Static and dynamic flow adhesion assays showed significantly increased adhesion of fluorescently labeled leukocytes to GPx1 KO PAECS and aortas respectively, which were significantly reduced by ebselen treatment. Our results suggest that GPx1 plays a critical role in regulating pro-inflammatory pathways, including MAPK and NF-κB, and down-stream mediators such as VCAM-1, in vascular endothelial cells. Lack of GPx1, via effects on p-AKT also affects signaling to eNOS-derived NO. We speculate based on these results that declining antioxidant defenses as seen in cardiovascular diseases, by failing to regulate these pro-inflammatory pathways, facilitates an inflammatory and activated endothelium leading to ED and atherogenesis.
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Lack of the antioxidant Glutathione Peroxidase-1 (GPx1) exacerbates retinopathy of prematurity in mice
Investigative Ophthalmology & Visual Science, 2013Co-Authors: Nada Stefanovic, Jennifer L. Wilkinson-berka, Judy B De HaanAbstract:Glutathione Peroxidase-1 (GPx1) is highly expressed during normal retinal maturation; however, its role in retinopathy of prematurity (ROP) is not fully understood. We postulated that GPx1 plays an important role in protecting the premature retina from oxidative injury in a mouse model of ROP. ROP was induced in wild-type (WT) and GPx1 knockout (KO) mice by exposing neonatal mice to 75% oxygen from postnatal days 7 to 11, followed by 1 week of room air. Structural effects of ROP were evaluated by retinal histology, and gene expression of retinal pro-angiogenic factors was measured by qRT-PCR. Retinas from ROP GPx1 KO mice had a significantly larger central avascular area compared to those from ROP WT mice (P < 0.001), indicative of a more severe vaso-obliteration. In ROP GPx1 KO mice, retinas also displayed increased preretinal neovascularization (P = 0.05) with a concurrent increase in the expression of vascular endothelial growth factor (P < 0.05) compared to values in ROP WT mice. Elevated oxidative stress was observed in ROP GPx1 KO retinas as evidenced by increased nitrotyrosine immunolabeling (P < 0.01) and superoxide (P < 0.05) in vessels compared to ROP WT retinas. In contrast to these findings of exacerbated retinal vascular injury in GPx1 KO mice, Müller cell gliosis and microglial density were similar in ROP GPx1 KO and ROP WT mice. GPx1, an important antioxidant enzyme of the premature retina, afforded protection against oxidative stress and oxidative injury in ROP. Lack of GPx1 was associated with increased oxidative stress, an increase in retinal avascular area, upregulation of retinal VEGF, and increased neovascularization in a mouse model of ROP.
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Retinal Light Damage: Structural and Functional Effects of the Antioxidant Glutathione Peroxidase-1
Investigative Ophthalmology & Visual Science, 2006Co-Authors: Andrew D. Gosbell, Nada Stefanovic, Lyndee L Scurr, Ismail Kola, Josefa Pete, Ian Favilla, Judy B De HaanAbstract:PURPOSE. The role of the antioxidant enzyme Glutathione Peroxidase-1 (GPx1) in protecting the retina against photo-oxidative damage was investigated in GPxl-deficient and wild-type mice. METHOD. Albino GPxl-deficient and age-matched wild-type mice were examined. Baseline electroretinograms (ERGs) were recorded. Thereafter, mice were exposed to intense light for 12 hours. After a 24-hour recovery in darkness, post-light-insult ERGs were recorded and compared with baseline. Structural effects of light insult were evaluated by retinal histology. Antioxidant expression was investigated by quantitative reverse transcription-PCR (qRT-PCR). RESULTS. light insult significantly affected ERG responses, with reduced a- and b-wave amplitudes. Structurally, photoreceptor layers were predominantly affected. As expected, GPxl expression was negligible in GPx1-deficient mice but was upregulated in wild-type mice in response to light insult. Similarly, hemeoxygenase-1 and thioredoxin-1 expression increased significantly in wild-type retinas after light exposure. Catalase, GPx isoforms (GPx2 to -4), peroxiredoxin-6, glutaredoxin-1, and thioredoxin-2 expression was unaffected by GPx1 deficiency and light insult, whereas significant increases in glutaredoxin-2 occurred in non-light-exposed (baseline) GPxl-deficient retinas. Compared with baseline wild-type retinas, lipid peroxidation (TBARS assay), an indicator of oxidative stress, was elevated in baseline GPx1-deficient retinas. Unexpectedly, the light insult induced diminution of retinal function, in terms of ERG amplitude, and structural damage was significantly greater in wild-type than in with GPx1-deficient retinas. CONCLUSIONS. The data showing increased oxidative damage in baseline GPx-deficient retina give rise to the hypothesis that increased oxidative stress provides a "preconditioning" environment in which protective mechanisms paradoxically render GPxl-deficient retinas less vulnerable to light-induced oxidative damage. This study identified glutaredoxin-2 as a potential candidate.