Cited by 186Platelet Disorders and TreatmentsBlood Coagulation and Thrombosis MechanismsSelenium in Biological Systems

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Glutathione Peroxidase-3 Deficiency Promotes Platelet-Dependent Thrombosis In Vivo

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Jin, Richard C., Mahoney, Christopher E., (Coleman) Anderson, Laura, Ottaviano, Filomena, Croce, Kevin, Leopold, Jane A., Zhang, Ying-Yi, Tang, Shiow-Shih, Handy, Diane E., Loscalzo, Joseph·2011·Circulation

DOI 10.1161/circulationaha.110.000034PMC PMC3107543

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Abstract

Background—: Glutathione peroxidase-3 (GPx-3) is a selenocysteine-containing plasma protein that scavenges reactive oxygen species in the extracellular compartment. A deficiency of this enzyme has been associated with platelet-dependent thrombosis, and a promoter haplotype with reduced function has been associated with stroke risk. Methods and Results—: We recently developed a genetic mouse model to assess platelet function and thrombosis in the setting of GPx-3 deficiency. The GPx-3(−/−)mice showed an attenuated bleeding time and an enhanced aggregation response to the agonist ADP compared with wild-type mice. GPx-3(−/−)mice displayed increased plasma levels of soluble P-selectin and decreased plasma cyclic cGMP compared with wild-type mice. ADP infusion-induced platelet aggregation in the pulmonary vasculature produced a more robust platelet activation response in the GPx-3(−/−)than wild-type mice; histological sections from the pulmonary vasculature of GPx-3(−/−)compared with wild-type mice showed increased platelet-rich thrombi and a higher percentage of occluded vessels. Cremaster muscle preparations revealed endothelial dysfunction in the GPx-3(−/−)compared with wild-type mice. With a no-flow ischemia-reperfusion stroke model, GPx-3(−/−)mice had significantly larger cerebral infarctions compared with wild-type mice and platelet-dependent strokes. To assess the neuroprotective role of antioxidants in this model, we found that manganese(III) meso-tetrakis(4-benzoic acid)porphyrin treatment reduced stroke size in GPx-3(−/−)mice compared with vehicle-treated controls. Conclusions—: These findings demonstrate that GPx-3 deficiency results in a prothrombotic state and vascular dysfunction that promotes platelet-dependent arterial thrombosis. These data illustrate the importance of this plasma antioxidant enzyme in regulating platelet activity, endothelial function, platelet-dependent thrombosis, and vascular thrombotic propensity.

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Restuadi, R., Steyn, F. J., Kabashi, E., Ngo, S. T., Cheng, F., Nabais, M. F., Thompson, M. J., Qi, T., Wu, Y., Henders, A. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18666693
Association of the GPx-3 + 1494 A/G gene polymorphism with serum trace elements in psoriasis vulgaris
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Additional file 2 of Associations between urinary heavy metal concentrations and blood pressure in residents of Asian countries
Mizuno, Y., Shimizu-Furusawa, H., Konishi, S., Inaoka, T., Ahmad, S. A., Sekiyama, M., Abdoellah, O. S., Gunawan, B., Parajuli, R. P., Ikemoto, Y., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16778372
Additional file 1 of Associations between urinary heavy metal concentrations and blood pressure in residents of Asian countries
Mizuno, Y., Shimizu-Furusawa, H., Konishi, S., Inaoka, T., Ahmad, S. A., Sekiyama, M., Abdoellah, O. S., Gunawan, B., Parajuli, R. P., Ikemoto, Y., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16778369
Additional file 2 of Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1
Restuadi, R., Steyn, F. J., Kabashi, E., Ngo, S. T., Cheng, F., Nabais, M. F., Thompson, M. J., Qi, T., Wu, Y., Henders, A. K., et al. (2022) · Figshare · doi:10.6084/m9.figshare.18666696
Expression patterns of glutathione peroxidases family members during tooth development
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Exploring the interplay between chronic thrombo-inflammation and megakaryopoiesis in the development of microvascular lesions during vasculitis-associated glomerulonephritis
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Aquaporin-1 facilitates the transport of hydrogen peroxide and nitric oxide during endothelium-dependent vasorelaxation
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Antioxidants in Oxidative Stress and Obesity-Associated Diseases: Molecular Mechanisms and Potential Health Implications
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Selenium-gene interactions involving microRNAs
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Authors: Jin, R. C., Mahoney, C. E., (Coleman) Anderson, L., Ottaviano, F., Croce, K., Leopold, J. A., Zhang, Y.-Y., Tang, S.-S., Handy, D. E., & Loscalzo, J.
Affiliations: Brigham and Women's Hospital (US)
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
ORCID: Mahoney, Christopher E.
Ottaviano, Filomena
Croce, Kevin
Leopold, Jane A.
Handy, Diane E.
Loscalzo, Joseph
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2011-05-10
Volume: 123
Issue: 18
Pages: 1963-1973
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.110.000034
PMC: PMC3107543
OpenAlex: W2058584041
Cited by: 186
References: 33
Citations by year: 2026: 5 · 2025: 13 · 2024: 16 · 2023: 13 · 2022: 22 · 2021: 11 · 2020: 7 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 19 · 2015: 13 · 2014: 11 · 2013: 14 · 2012: 5
FWCI: 8.10
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (n01hv28178-12-0-0)
National Heart, Lung, and Blood Institute (HL 089734, HL081587, HL 070819, K08HL086672, U54HL070819, HL086672, P01HL081587, N01-HV-028178, R21HL089734, R01HL105301, P01HL048743, HL-061795, R37HL061795)
Topics: Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Health Sciences › Nursing › Nutrition and Dietetics › Selenium in Biological Systems
Keywords: glutathione peroxidase 3, platelet aggregation, ADP-induced aggregation, soluble P-selectin, pulmonary vasculature, endothelial dysfunction, cerebral infarction, manganese porphyrin, antioxidants, reactive oxygen species, selenocysteine, genetic mouse models
MeSH terms: Adenosine Diphosphate, Animals, Antioxidants, Bleeding Time, Blood Platelets, Disease Models, Animal, Endothelium, Vascular, Genotype, Glutathione, Glutathione Peroxidase, Cyclic GMP, Platelet Aggregation, Risk Factors, Thrombosis, Reactive Oxygen Species, Mice, Knockout, P-Selectin, Infarction, Middle Cerebral Artery, Mice

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Glutathione Peroxidase-3 Deficiency Promotes Platelet-Dependent Thrombosis In Vivo

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