Abstract 54: Overexpression of Glutathione Peroxidase-1 Protects Mice from Aging-Related Enhancement of Experimental Thrombosis and Platelet Activation
Despite a well-established clinical association between aging and thrombosis, little is known about the mechanisms by which aging increases susceptibility to thrombotic events such as stroke, myocardial infarction, and deep venous thrombosis. Since aging is associated with increased levels of reactive oxygen species and decreased levels of the antioxidant enzyme glutathione peroxidase (Gpx), we tested the hypothesis that overexpression of a cellular form of Gpx (Gpx1) protects aged mice from increased thrombotic susceptibility. Susceptibility to arterial thrombosis was first examined in C57BL/6J mice at 4, 12, or 18 months of age. The time to stable occlusion after photochemical injury of the carotid artery was significantly shortened in both 12 and 18 month old mice compared to 4 month old mice (P<0.01). To examine the protective role of Gpx1, transgenic mice overexpressing Gpx1 (Gpx1 Tg mice) were studied. Unlike wild type littermates, no shortening of the time to occlusion of the carotid artery was seen in 12 or 18 month old Gpx1 Tg mice. In addition, we also found that aged wild type mice exhibited increased susceptibility to venous thrombosis, and that overexpression of Gpx1 was protective in an inferior vena cava stasis model. An age-dependent increase in platelet hydrogen peroxide generation was observed in thrombin-activated platelets from wild type mice but not Gpx1 Tg mice (P<0.05). Markers of platelet activation, including fibrinogen binding and activation of αIIbβ3, were also increased in thrombin-activated platelets from aged mice compared to young mice (P<0.05). Overexpression of Gpx1 or treatment with catalase prevented these enhanced platelet activation responses in platelets from aged mice. Our findings demonstrate that aged mice exhibit increased susceptibility to both arterial and venous thrombosis and that enhanced thrombosis and platelet activation in aged mice are mediated by peroxide. Therapeutic strategies to prevent the accumulation of hydrogen peroxide in platelets may reduce the incidence of aging-associated thrombosis.
- © 2012 by American Heart Association, Inc.