title: Glutathione peroxidase-3 deficiency promotes platelet-dependent thrombosis in vivo.
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.
  
  
  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.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Jin
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mahoney
authors.forename: Laura
authors.initials: L
authors.lastname: Coleman Anderson
authors.forename: Filomena
authors.initials: F
authors.lastname: Ottaviano
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Zhang
authors.forename: Shiow-Shih
authors.initials: SS
authors.lastname: Tang
authors.forename: Diane E
authors.initials: DE
authors.lastname: Handy
authors.forename: Joseph
authors.initials: J
authors.lastname: Loscalzo
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000097:blood; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000502:physiology; D005838:Genotype; D005978:Glutathione / Q000097:blood; D005979:Glutathione Peroxidase / Q000235:genetics* / Q000378:metabolism*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012307:Risk Factors; D013927:Thrombosis / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D019007:P-Selectin; D017382:Reactive Oxygen Species; D000244:Adenosine Diphosphate; C116888:Gpx3 protein, mouse; D005979:Glutathione Peroxidase; D005978:Glutathione; D006152:Cyclic GMP