Abstract 5302: Glutathione Peroxidase-3 Deficiency Promotes Platelet-dependent Thrombosis and Thrombotic Stroke in vivo
Plasma glutathione peroxidase (GPx-3) is a selenocysteine-containing protein with antioxidant activity. GPx-3 plays an important role in plasma by scavenging reactive oxygen species. We have previously shown that a heritable deficiency of this enzyme is associated with platelet-dependent thrombotic stroke in patients. We recently developed a GPx-3 knockout mouse to assess platelet function and platelet-dependent thrombosis in models of vascular injury. We hypothesized that GPx-3 deficiency promotes platelet-dependent thrombus formation in vivo. GPx-3 (−/−) mice showed an attenuated bleeding time compared with wild-type mice (94.5±28.8 s versus 153.4±32.3, P<0.05). We also noted an increase in the plasma levels of soluble P-selectin, a marker of platelet activation and prothrombotic activity, in GPx-3 (−/−) mice compared with wild-type mice (137.8±12.3 ng/ml plasma versus 101.5±8.8, P<0.05). Using a no-flow ischemia-reperfusion stroke model, we found that GPx-3 (−/−) mice had significantly larger cerebral infarctions compared with wild-type mice (117.5±7.9 mm3 versus 17.2±2.7, P<0.001) as well as higher neurological deficit scores (3.33±0.33 versus 1.3±0.33, P=0.02). To investigate the effect of platelet inhibition on stroke size in GPx-3 deficiency, GPx-3 deficient mice were pre-treated with clopidogrel prior to producing the stroke. We found that clopidogrel treatment reduced stroke size significantly compared with vehicle-treated controls (4.42±3.0 mm3 versus 105.1±15.2, P=0.003) as well as lowered neurological deficit scores (0.4±0.2 versus 2.83±0.44, P=0.018). These findings demonstrate that GPx-3 deficiency promotes platelet activation resulting in a prothrombotic state. These data illustrate the importance of this plasma antioxidant enzyme in regulating platelet activity, platelet-dependent thrombosis, and vascular thrombotic propensity.