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

Article

关键词: HYDROGEN-PEROXIDE;    NITRIC-OXIDE;    RETICULUM CA2+-ATPASE;    ARTERIAL THROMBOSIS;    SUPEROXIDE ANION;    RISK-FACTOR;    GPX-3 GENE;    ACTIVATION;    PLASMA;    PEROXYNITRITE;   

DOI  :  10.1161/CIRCULATIONAHA.110.000034

来源: SCIE

【 摘 要 】

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. (Circulation. 2011;123:1963-1973.)

【 授权许可】

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