title: Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis.
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.
  
  
  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 p47(phox) 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.
authors: Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr, 3160 ML, Iowa City, IA 52242, USA. sanjana-dayal@uiowa.edu.
authors: Sanjana
authors: S
authors: Dayal
authors: Katina M
authors: KM
authors: Wilson
authors: David G
authors: DG
authors: Motto
authors: Francis J
authors: FJ
authors: Miller
authors: Anil K
authors: AK
authors: Chauhan
authors: Steven R
authors: SR
authors: Lentz
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002374:Catalase / Q000494:pharmacology; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D011092:Polyethylene Glycols / Q000494:pharmacology; D012307:Risk Factors; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013927:Thrombosis / Q000453:epidemiology* / Q000378:metabolism* / Q000503:physiopathology; D000094765:Glutathione Peroxidase GPX1
chemical_list: D000098:Acetophenones; C070295:catalase-polyethylene glycol; D011092:Polyethylene Glycols; C056165:acetovanillone; D006861:Hydrogen Peroxide; D002374:Catalase; D005979:Glutathione Peroxidase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000094765:Glutathione Peroxidase GPX1; C000722068:Gpx1 protein, mouse