Logo image
Back
Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis
Journal article   Open access   Peer reviewed

Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis

Sanjana Dayal, Katina M Wilson, David G Motto, Francis J Miller Jr, Anil K Chauhan and Steven R Lentz
Circulation (New York, N.Y.), Vol.127(12), pp.1308-1316
03/26/2013
DOI: 10.1161/CIRCULATIONAHA.112.000966
PMCID: PMC4447136
PMID: 23426106
url
https://doi.org/10.1161/CIRCULATIONAHA.112.000966View
Published (Version of record) Open Access

Abstract

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 versus 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, was 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 polyethylene glycol–catalase or apocynin, an inhibitor of NADPH oxidase. Aged mice displayed increased intraplatelet expression of p47phox and superoxide dismutase-1, suggesting a mechanistic pathway for increased hydrogen peroxide generation. Conclusions— Our findings demonstrate that hydrogen peroxide is a key mediator of platelet hyperactivity and enhanced thrombotic susceptibility in aged mice.
 Catalase - pharmacology Oxidative Stress - physiology NADPH Oxidases - metabolism Platelet Activation - physiology Male Acetophenones - pharmacology Female Models, Animal Superoxide Dismutase - metabolism Polyethylene Glycols - pharmacology Glutathione Peroxidase - metabolism Thrombosis - physiopathology Mice, Inbred C57BL NADPH Oxidases - antagonists & inhibitors Risk Factors Mice, Transgenic Thrombosis - epidemiology Glutathione Peroxidase - genetics Hydrogen Peroxide - metabolism Thrombosis - metabolism Animals Blood Platelets - metabolism Mice Platelet Activation - drug effects Superoxide Dismutase-1 Aging - metabolism

Details

Metrics

16 Record Views
175 Times Cited - Web of Science
Logo image