Plasma Glutathione Peroxidase Activity is Potentially a Key Regulator of Vascular Disease-Associated Thrombosis

In the current issue of Circulation , Jin et al1 provide insight into how a deficiency in the activity of the primary plasma peroxide-metabolizing enzyme glutathione peroxidase-3 (GPx-3) creates a prothrombotic state with vascular dysfunction. Mice deficient in GPx-3 are shown to have elevated soluble P-selectin (a marker of platelet and prothrombotic activity) and enhanced responses to experimental conditions promoting pulmonary thromboembolism and platelet-dependent cerebral infarctions in a no-flow ischemia–reperfusion stroke model. Initial studies on the properties of platelet aggregation in 2 brothers with a cerebral thrombotic disorder identified a deficiency in plasma glutathione peroxidase activity as a key factor explaining the hyperreactivity of their platelets.2 Subsequent studies examining the consequences of promoter polymorphisms in the human GPx-3 gene associated with decreases in plasma GPx-3 expression provided evidence that it was a risk factor for ischemic stroke in young adults and children.3 A deficiency in GPx-3 has been associated with increases in extracellular peroxide-related oxidants and decreased bioavailable nitric oxide that are thought to contribute to promoting platelet activation.2,4 Thus, plasma glutathione peroxidase activity may be a key factor in determining when disease processes activating platelets result in arterial thrombosis.Article see p 1963It is well established that increased peroxide levels in plasma promote platelet hyperreactivity, and that nitric oxide is a key mechanism for inhibiting platelet aggregation and vasoconstriction associated with thrombosis. As discussed in the article by Jin et al,1 platelet activation generates superoxide and peroxides that appear to promote aggregation by mechanisms including peroxide-mediated stimulation of intracellular calcium release, which …