Journal article
Deficiency of superoxide dismutase impairs protein C activation and enhances susceptibility to experimental thrombosis
Arteriosclerosis, thrombosis, and vascular biology, Vol.35(8), pp.1798-1804
08/2015
DOI: 10.1161/ATVBAHA.115.305963
PMCID: PMC4514539
PMID: 26069236
Abstract
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.
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).
SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous thrombosis in mice.
Details
- Title: Subtitle
- Deficiency of superoxide dismutase impairs protein C activation and enhances susceptibility to experimental thrombosis
- Creators
- Sanjana Dayal - 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.eduSean X Gu - 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, SeattleRyan D Hutchins - 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, SeattleKatina M Wilson - 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, SeattleYi Wang - 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, SeattleXiaoyun Fu - 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, SeattleSteven R Lentz - 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
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.35(8), pp.1798-1804
- Publisher
- United States
- DOI
- 10.1161/ATVBAHA.115.305963
- PMID
- 26069236
- PMCID
- PMC4514539
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Grant note
- HL063943 / NHLBI NIH HHS NS024621 / NINDS NIH HHS R01 HL063943 / NHLBI NIH HHS P01 NS024621 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS
- Language
- English
- Date published
- 08/2015
- Academic Unit
- Iowa Technology Institute; Hematology, Oncology, and Blood & Marrow Transplantation; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984065483102771
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