Hydrogen Peroxide Promotes Aging-Related Platelet Hyperactivation and Thrombosis
Background—The incidence of thrombotic events increases during aging but the mechanisms are not well understood. To investigate the prothrombotic role of oxidative stress during aging, we tested the hypothesis that aged mice overexpressing the antioxidant enzyme glutathione peroxidase-1 (Gpx1) are protected from experimental thrombosis.
Methods and Results—Susceptibility to carotid artery thrombosis was first examined in wild-type C57BL/6J mice. After photochemical injury of the carotid artery, the time to stable occlusion was significantly shorter in 12 and 18 month old mice compared with 4 month old mice (P<0.01). Unlike wild-type mice, transgenic mice overexpressing Gpx1 (Gpx1 Tg) did not exhibit shortened times to occlusion of the carotid artery at 12 or 18 months of age. Wild-type mice also exhibited increased susceptibility to venous thrombosis after inferior vena cava ligation at 12 or 18 months of age (P<0.05 vs. 4 months of age). Gpx1 Tg mice were protected from this aging-related enhanced susceptibility to venous thrombosis. Age-dependent platelet hyperactivation, evidenced by increased hydrogen peroxide, fibrinogen binding, and activation of fibrinogen receptor αIIbβ3, were observed in thrombin-activated platelets from wild-type but not Gpx1 Tg mice (P<0.05). Enhanced platelet activation responses in aged mice were also prevented by PEG-catalase or apocynin, an inhibitor of NADPH oxidase. Aged mice displayed increased intra-platelet expression of p47phox and superoxide dismutase-1, suggesting a mechanistic pathway for increased H2O2 generation.
Conclusions—Our findings demonstrate that hydrogen peroxide is a key mediator of platelet hyperactivity and enhanced thrombotic susceptibility in aged mice.
- Received December 28, 2012.
- Revision received February 6, 2013.
- Accepted February 8, 2013.
- Copyright © 2013, Circulation