title: Deficiency of superoxide dismutase impairs protein C activation and enhances susceptibility to experimental thrombosis.
abstract: OBJECTIVE
  Clinical evidence suggests an association between oxidative stress and vascular disease, and in vitro studies have demonstrated that reactive oxygen species can have prothrombotic effects on vascular and blood cells. It remains unclear, however, whether elevated levels of reactive oxygen species accelerate susceptibility to experimental thrombosis in vivo.
  
  
  RESULTS
  Using a murine model with genetic deficiency in superoxide dismutase-1 (SOD1), we measured susceptibility to carotid artery thrombosis in response to photochemical injury. We found that SOD1-deficient (Sod1(-/-)) mice formed stable arterial occlusions significantly faster than wild-type (Sod1(+/+)) mice (P<0.05). Sod1(-/-) mice also developed significantly larger venous thrombi than Sod1(+/+) mice after inferior vena cava ligation (P<0.05). Activation of protein C by thrombin in lung was diminished in Sod1(-/-) mice (P<0.05 versus Sod1(+/+) mice), and generation of activated protein C in response to infusion of thrombin in vivo was decreased in Sod1(-/-) mice (P<0.05 versus Sod1(+/+) mice). SOD1 deficiency had no effect on the expression of thrombomodulin, endothelial protein C receptor, or tissue factor in lung or levels of protein C in plasma. Exposure of human thrombomodulin to superoxide in vitro caused oxidation of multiple methionine residues, including critical methionine 388, and a 40% decrease in thrombomodulin-dependent activation of protein C (P<0.05). SOD and catalase protected against superoxide-induced methionine oxidation and restored protein C activation in vitro (P<0.05).
  
  
  CONCLUSIONS
  SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous thrombosis in mice.
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle. sanjana-dayal@uiowa.edu.
authors.forename: Sanjana
authors.initials: S
authors.lastname: Dayal
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle.
authors.forename: Sean X
authors.initials: SX
authors.lastname: Gu
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Hutchins
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle.
authors.forename: Katina M
authors.initials: KM
authors.lastname: Wilson
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Fu
authors.affiliation: From the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (S.D., S.X.G., R.D.H., K.M.W., S.R.L.); and BloodWorks Northwest Research Institute (Y.W., X.F.) and Department of Medicine (X.F.), University of Washington, Seattle.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Lentz
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017536:Carotid Artery, Common / Q000201:enzymology / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006801:Humans; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011486:Protein C / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000172:deficiency* / Q000235:genetics; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000378:metabolism; D018180:Thrombomodulin / Q000378:metabolism; D013927:Thrombosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014682:Vena Cava, Inferior / Q000201:enzymology / Q000473:pathology; D020246:Venous Thrombosis / Q000201:enzymology* / Q000473:pathology
chemical_list: D011486:Protein C; C000606290:SOD1 protein, human; C546931:THBD protein, human; D018180:Thrombomodulin; D013481:Superoxides; D002374:Catalase; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: catalase; protein C; superoxides; thrombomodulin; thrombosis