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Steven R. Lentz - One of the best experts on this subject based on the ideXlab platform.
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deficiency of superoxide dismutase impairs protein c activation and enhances susceptibility to Experimental Thrombosis
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Sanjana Dayal, Katina M. Wilson, Ryan Hutchins, Yi Wang, Steven R. LentzAbstract: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. Approach and 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 Sod1 −/− mice also developed significantly larger venous thrombi than Sod1 +/+ mice after inferior vena cava ligation ( P Sod1 −/− mice ( P Sod1 +/+ mice), and generation of activated protein C in response to infusion of thrombin in vivo was decreased in Sod1 −/− mice ( P 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 P Conclusions— SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous Thrombosis in mice.
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abstract 34 endogenous superoxide dismutase protects from impaired generation of activated protein c and enhanced susceptibility to Experimental Thrombosis in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Sanjana Dayal, Ryan Hutchins, Katinan M Wilson, Steven R. LentzAbstract:In vitro studies have suggested that reactive oxygen species such as superoxide can produce prothrombotic effects, including enhanced platelet activation, increased tissue factor (TF) expression, and an oxidative modification in thrombomodulin impairing its capacity to enhance the generation of activated protein C (APC) by thrombin. It is not known, however, if elevated levels of superoxide accelerate susceptibility to Experimental Thrombosis in vivo . We used mice genetically deficient in superoxide dismutase-1 (SOD1, an antioxidant enzyme that dismutates superoxide to hydrogen peroxide), to test the hypothesis that lack of SOD1 enhances susceptibility to Thrombosis. Susceptibility to carotid artery Thrombosis in a photochemical injury model demonstrated that Sod1-/- mice formed stable occlusions significantly faster than Sod1+/+ mice (P<0.05). In an inferior vena cava (IVC) stasis model Sod1- /- mice developed significantly larger thrombi 48 hours after IVC ligation (P<0.05 vs. Sod1+/+ mice). After activation with thrombin (0.5 U/ml) or convulxin (200 ng/ml), no differences in surface expression of P-selectin or binding of fibrinogen were observed between platelets from Sod1-/- and Sod1+/+ mice. The expression of TF mRNA in lung measured by real time qPCR showed similar levels in Sod1-/- and Sod1 +/+ mice. However, the activation of exogenous protein C by thrombin in lung homogenates was decreased in Sod1 -/- mice (P<0.05 vs. Sod1 +/+ mice). Further, in vivo generation of activated protein C in response to thrombin (40 U/Kg) infusion was significantly lower in Sod1-/- mice (P<0.05 vs. Sod1+/+ mice). No differences in mRNA levels for thrombomodulin or endothelial protein C receptor were detected in Sod1 -/- mice vs. Sod1 +/+ mice, suggesting that altered generation of activated protein C in Sod1-/- mice may be related to a direct oxidative effect on thrombomodulin. In accordance, thrombomodulin treated with xanthine/hypoxanthine showed 40% loss of ability to activate protein C that was overcome by addition of SOD and catalase (P<0.05). We conclude that endogenous SOD1 in mice protects from impaired generation of activated protein C and accelerated Thrombosis.
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hydrogen peroxide promotes aging related platelet hyperactivation and Thrombosis
Circulation, 2013Co-Authors: Sanjana Dayal, Katina M. Wilson, David G Motto, Francis J Miller, Anil K Chauhan, Steven R. LentzAbstract: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 s...
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abstract 54 overexpression of glutathione peroxidase 1 protects mice from aging related enhancement of Experimental Thrombosis and platelet activation
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Sanjana Dayal, Katina M. Wilson, Steven R. LentzAbstract:Despite a well-established clinical association between aging and Thrombosis, little is known about the mechanisms by which aging increases susceptibility to thrombotic events such as stroke, myocardial infarction, and deep venous Thrombosis. Since aging is associated with increased levels of reactive oxygen species and decreased levels of the antioxidant enzyme glutathione peroxidase (Gpx), we tested the hypothesis that overexpression of a cellular form of Gpx (Gpx1) protects aged mice from increased thrombotic susceptibility. Susceptibility to arterial Thrombosis was first examined in C57BL/6J mice at 4, 12, or 18 months of age. The time to stable occlusion after photochemical injury of the carotid artery was significantly shortened in both 12 and 18 month old mice compared to 4 month old mice (P<0.01). To examine the protective role of Gpx1, transgenic mice overexpressing Gpx1 (Gpx1 Tg mice) were studied. Unlike wild type littermates, no shortening of the time to occlusion of the carotid artery was see...
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deficiency of superoxide dismutase impairs generation of activated protein c and enhances susceptibility to Experimental Thrombosis in mice
Blood, 2011Co-Authors: Sanjana Dayal, Katina M. Wilson, Ryan Hutchins, Steven R. LentzAbstract:Abstract Abstract 535 In vitro studies have suggested that reactive oxygen species such as superoxide can produce several potentially prothrombotic effects, including enhanced platelet activation, increased tissue factor (TF) expression, and an oxidative modification in thrombomodulin that impairs its capacity to enhance the generation of activated protein C (APC) by thrombin. It is not known, however, if elevated levels of superoxide accelerate susceptibility to Experimental Thrombosis in vivo. Using a murine model that is genetically deficient in superoxide dismutase-1 (SOD1, an antioxidant enzyme that dismutates superoxide to hydrogen peroxide), we tested the hypothesis that lack of superoxide dismutase enhances susceptibility to Thrombosis. Additionally, we investigated the mechanisms of superoxide-enhanced Thrombosis. First, we examined the susceptibility to carotid artery Thrombosis in a photochemical injury model. We found that Sod1−/− mice formed stable occlusions significantly faster than Sod1+/+ or Sod1+/− mice (P Disclosures: No relevant conflicts of interest to declare.
Sanjana Dayal - One of the best experts on this subject based on the ideXlab platform.
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deficiency of superoxide dismutase impairs protein c activation and enhances susceptibility to Experimental Thrombosis
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Sanjana Dayal, Katina M. Wilson, Ryan Hutchins, Yi Wang, Steven R. LentzAbstract: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. Approach and 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 Sod1 −/− mice also developed significantly larger venous thrombi than Sod1 +/+ mice after inferior vena cava ligation ( P Sod1 −/− mice ( P Sod1 +/+ mice), and generation of activated protein C in response to infusion of thrombin in vivo was decreased in Sod1 −/− mice ( P 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 P Conclusions— SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous Thrombosis in mice.
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abstract 34 endogenous superoxide dismutase protects from impaired generation of activated protein c and enhanced susceptibility to Experimental Thrombosis in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2014Co-Authors: Sanjana Dayal, Ryan Hutchins, Katinan M Wilson, Steven R. LentzAbstract:In vitro studies have suggested that reactive oxygen species such as superoxide can produce prothrombotic effects, including enhanced platelet activation, increased tissue factor (TF) expression, and an oxidative modification in thrombomodulin impairing its capacity to enhance the generation of activated protein C (APC) by thrombin. It is not known, however, if elevated levels of superoxide accelerate susceptibility to Experimental Thrombosis in vivo . We used mice genetically deficient in superoxide dismutase-1 (SOD1, an antioxidant enzyme that dismutates superoxide to hydrogen peroxide), to test the hypothesis that lack of SOD1 enhances susceptibility to Thrombosis. Susceptibility to carotid artery Thrombosis in a photochemical injury model demonstrated that Sod1-/- mice formed stable occlusions significantly faster than Sod1+/+ mice (P<0.05). In an inferior vena cava (IVC) stasis model Sod1- /- mice developed significantly larger thrombi 48 hours after IVC ligation (P<0.05 vs. Sod1+/+ mice). After activation with thrombin (0.5 U/ml) or convulxin (200 ng/ml), no differences in surface expression of P-selectin or binding of fibrinogen were observed between platelets from Sod1-/- and Sod1+/+ mice. The expression of TF mRNA in lung measured by real time qPCR showed similar levels in Sod1-/- and Sod1 +/+ mice. However, the activation of exogenous protein C by thrombin in lung homogenates was decreased in Sod1 -/- mice (P<0.05 vs. Sod1 +/+ mice). Further, in vivo generation of activated protein C in response to thrombin (40 U/Kg) infusion was significantly lower in Sod1-/- mice (P<0.05 vs. Sod1+/+ mice). No differences in mRNA levels for thrombomodulin or endothelial protein C receptor were detected in Sod1 -/- mice vs. Sod1 +/+ mice, suggesting that altered generation of activated protein C in Sod1-/- mice may be related to a direct oxidative effect on thrombomodulin. In accordance, thrombomodulin treated with xanthine/hypoxanthine showed 40% loss of ability to activate protein C that was overcome by addition of SOD and catalase (P<0.05). We conclude that endogenous SOD1 in mice protects from impaired generation of activated protein C and accelerated Thrombosis.
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hydrogen peroxide promotes aging related platelet hyperactivation and Thrombosis
Circulation, 2013Co-Authors: Sanjana Dayal, Katina M. Wilson, David G Motto, Francis J Miller, Anil K Chauhan, Steven R. LentzAbstract: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 s...
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abstract 54 overexpression of glutathione peroxidase 1 protects mice from aging related enhancement of Experimental Thrombosis and platelet activation
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Sanjana Dayal, Katina M. Wilson, Steven R. LentzAbstract:Despite a well-established clinical association between aging and Thrombosis, little is known about the mechanisms by which aging increases susceptibility to thrombotic events such as stroke, myocardial infarction, and deep venous Thrombosis. Since aging is associated with increased levels of reactive oxygen species and decreased levels of the antioxidant enzyme glutathione peroxidase (Gpx), we tested the hypothesis that overexpression of a cellular form of Gpx (Gpx1) protects aged mice from increased thrombotic susceptibility. Susceptibility to arterial Thrombosis was first examined in C57BL/6J mice at 4, 12, or 18 months of age. The time to stable occlusion after photochemical injury of the carotid artery was significantly shortened in both 12 and 18 month old mice compared to 4 month old mice (P<0.01). To examine the protective role of Gpx1, transgenic mice overexpressing Gpx1 (Gpx1 Tg mice) were studied. Unlike wild type littermates, no shortening of the time to occlusion of the carotid artery was see...
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deficiency of superoxide dismutase impairs generation of activated protein c and enhances susceptibility to Experimental Thrombosis in mice
Blood, 2011Co-Authors: Sanjana Dayal, Katina M. Wilson, Ryan Hutchins, Steven R. LentzAbstract:Abstract Abstract 535 In vitro studies have suggested that reactive oxygen species such as superoxide can produce several potentially prothrombotic effects, including enhanced platelet activation, increased tissue factor (TF) expression, and an oxidative modification in thrombomodulin that impairs its capacity to enhance the generation of activated protein C (APC) by thrombin. It is not known, however, if elevated levels of superoxide accelerate susceptibility to Experimental Thrombosis in vivo. Using a murine model that is genetically deficient in superoxide dismutase-1 (SOD1, an antioxidant enzyme that dismutates superoxide to hydrogen peroxide), we tested the hypothesis that lack of superoxide dismutase enhances susceptibility to Thrombosis. Additionally, we investigated the mechanisms of superoxide-enhanced Thrombosis. First, we examined the susceptibility to carotid artery Thrombosis in a photochemical injury model. We found that Sod1−/− mice formed stable occlusions significantly faster than Sod1+/+ or Sod1+/− mice (P Disclosures: No relevant conflicts of interest to declare.
B J Biemond - One of the best experts on this subject based on the ideXlab platform.
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prevention and treatment of Experimental Thrombosis in rabbits with rivaroxaban bay 597939 an oral direct factor xa inhibitor
Thrombosis and Haemostasis, 2007Co-Authors: B J Biemond, Philip W Friederich, Marcel Levi, Elisabeth Perzborn, Ulf Buetehorn, Harry R BullerAbstract:Current anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of Experimental venous Thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous Thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fondaparinux (42 microg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabelled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED(50) 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondaparinux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous Thrombosis in two well-established models of Experimental Thrombosis.
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enhancement of rabbit jugular vein thrombolysis by neutralization of factor xi in vivo evidence for a role of factor xi as an anti fibrinolytic factor
Journal of Clinical Investigation, 1998Co-Authors: M C Minnema, Joost C M Meijers, Laurent O Mosnier, Philip W Friederich, Marcel Levi, P A K Von Dem Borne, B J Biemond, C E Hack, B N Bouma, Ten H CateAbstract:Recent in vitro studies have shown that fibrinolytic activity may be attenuated by a thrombin-activatable fibrinolysis inhibitor (TAFI), which is activated by thrombin, generated via the intrinsic pathway of coagulation in a factor XI-dependent way. Thus factor XI may play a role in the regulation of endogenous fibrinolysis. The aim of this study was to investigate the effect of in vivo inhibition of factor XI and TAFI in an Experimental Thrombosis model in rabbits. Incorporation of anti-factor XI antibodies in jugular vein thrombi resulted in an almost twofold increase in endogenous thrombolysis compared with a control antibody. A similar effect was observed when the anti-factor XI antibody was administered systemically. Inhibition of TAFI activity also resulted in a twofold increase in clot lysis whereas inhibition of both factor XI and TAFI activity had no additional effect. Thus, we provide the first in vivo evidence for enhanced thrombolysis through inhibition of clotting factor XI, demonstrating a novel role for the intrinsic pathway of coagulation. Furthermore we demonstrate that inhibition of TAFI had a similar effect on thrombolysis. We postulate that inhibition of factor XI activity enhances thrombolysis because of diminished indirect activation of TAFI.
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comparison of sustained antithrombotic effects of inhibitors of thrombin and factor xa in Experimental Thrombosis
Circulation, 1996Co-Authors: B J Biemond, Philip W Friederich, M Levi, George P Vlasuk, H R Buller, J Ten W CateAbstract:Background In the pathogenesis of (recurrent) Thrombosis, clot-associated thrombin appears to play an important role. Antithrombin III–independent thrombin inhibitors have been shown to neutralize clot-bound thrombin effectively. We compared the sustained antithrombotic effects and the effects on endogenous fibrinolysis of several of these agents with recombinant tick anticoagulant peptide (rTAP), a selective factor Xa inhibitor, and low-molecular-weight heparin (LMWH) in an Experimental venous Thrombosis model. Methods and Results Rabbits received either recombinant hirudin (rHir), Hirulog-1, CVS#995 (a novel direct inhibitor of thrombin), rTAP, LMWH, or saline. The effect on thrombus growth was assessed by measuring the accretion of 125I-labeled fibrinogen onto preformed nonradioactive thrombi, and the effect on endogenous fibrinolysis was assessed by measuring the decline in radioactivity of preformed 125I-labeled thrombi in rabbit jugular veins. All direct thrombin inhibitors induced a sustained antit...
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inhibition of plasminogen activator inhibitor 1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of Experimental Thrombosis
Circulation, 1992Co-Authors: Marcel Levi, B J Biemond, J Ten W Cate, A J Van Zonneveld, Hans PannekoekAbstract:BACKGROUND We investigated the effect of inhibition of plasminogen activator inhibitor-1 (PAI-1) activity by a murine monoclonal anti-human PAI-1 antibody (MAI-12) on in vitro thrombolysis and on in vivo thrombolysis and thrombus extension in an Experimental animal model for Thrombosis. METHODS AND RESULTS Thrombolysis, mediated by recombinant tissue-type plasminogen activator (rt-PA), was studied in an in vitro system consisting of fibrinogen, plasminogen, and thrombin. Addition of purified platelets during clot formation inhibited rt-PA-mediated thrombolysis in a dose-dependent manner. Platelet-dependent thrombolysis resistance could be completely neutralized by the monoclonal antibody MAI-12, supporting the notion that the observed resistance is due to PAI-1 released from alpha-granules of platelets. Subsequently, we monitored in vivo thrombolysis and thrombus extension of human whole blood thrombi that were allowed to form in rabbit jugular veins. During thrombus formation, either MAI-12 or an irrelevant antibody was incorporated. Thrombolysis and thrombus extension were simultaneously measured during endogenous thrombolysis or upon administration of different dosages of rt-PA. We observed that endogenous thrombolysis was enhanced in the presence of MAI-12 compared with the control antibody. Significantly, thrombus extension was partially prevented by MAI-12 and not by the control antibody irrespective of whether exogenous rt-PA was systematically administered. CONCLUSIONS These observations further confirm the essential role of PAI-1 in the regulation of the thrombolytic system and support the exploration of adjunctive therapy based on inhibition of PAI-1 activity in thrombolytic strategies.
Katina M. Wilson - One of the best experts on this subject based on the ideXlab platform.
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deficiency of superoxide dismutase impairs protein c activation and enhances susceptibility to Experimental Thrombosis
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Sanjana Dayal, Katina M. Wilson, Ryan Hutchins, Yi Wang, Steven R. LentzAbstract: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. Approach and 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 Sod1 −/− mice also developed significantly larger venous thrombi than Sod1 +/+ mice after inferior vena cava ligation ( P Sod1 −/− mice ( P Sod1 +/+ mice), and generation of activated protein C in response to infusion of thrombin in vivo was decreased in Sod1 −/− mice ( P 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 P Conclusions— SOD prevents thrombomodulin methionine oxidation, promotes protein C activation, and protects against arterial and venous Thrombosis in mice.
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hydrogen peroxide promotes aging related platelet hyperactivation and Thrombosis
Circulation, 2013Co-Authors: Sanjana Dayal, Katina M. Wilson, David G Motto, Francis J Miller, Anil K Chauhan, Steven R. LentzAbstract: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 s...
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abstract 54 overexpression of glutathione peroxidase 1 protects mice from aging related enhancement of Experimental Thrombosis and platelet activation
Arteriosclerosis Thrombosis and Vascular Biology, 2012Co-Authors: Sanjana Dayal, Katina M. Wilson, Steven R. LentzAbstract:Despite a well-established clinical association between aging and Thrombosis, little is known about the mechanisms by which aging increases susceptibility to thrombotic events such as stroke, myocardial infarction, and deep venous Thrombosis. Since aging is associated with increased levels of reactive oxygen species and decreased levels of the antioxidant enzyme glutathione peroxidase (Gpx), we tested the hypothesis that overexpression of a cellular form of Gpx (Gpx1) protects aged mice from increased thrombotic susceptibility. Susceptibility to arterial Thrombosis was first examined in C57BL/6J mice at 4, 12, or 18 months of age. The time to stable occlusion after photochemical injury of the carotid artery was significantly shortened in both 12 and 18 month old mice compared to 4 month old mice (P<0.01). To examine the protective role of Gpx1, transgenic mice overexpressing Gpx1 (Gpx1 Tg mice) were studied. Unlike wild type littermates, no shortening of the time to occlusion of the carotid artery was see...
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deficiency of superoxide dismutase impairs generation of activated protein c and enhances susceptibility to Experimental Thrombosis in mice
Blood, 2011Co-Authors: Sanjana Dayal, Katina M. Wilson, Ryan Hutchins, Steven R. LentzAbstract:Abstract Abstract 535 In vitro studies have suggested that reactive oxygen species such as superoxide can produce several potentially prothrombotic effects, including enhanced platelet activation, increased tissue factor (TF) expression, and an oxidative modification in thrombomodulin that impairs its capacity to enhance the generation of activated protein C (APC) by thrombin. It is not known, however, if elevated levels of superoxide accelerate susceptibility to Experimental Thrombosis in vivo. Using a murine model that is genetically deficient in superoxide dismutase-1 (SOD1, an antioxidant enzyme that dismutates superoxide to hydrogen peroxide), we tested the hypothesis that lack of superoxide dismutase enhances susceptibility to Thrombosis. Additionally, we investigated the mechanisms of superoxide-enhanced Thrombosis. First, we examined the susceptibility to carotid artery Thrombosis in a photochemical injury model. We found that Sod1−/− mice formed stable occlusions significantly faster than Sod1+/+ or Sod1+/− mice (P Disclosures: No relevant conflicts of interest to declare.
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effect of mechanical ventilation on carotid artery Thrombosis induced by photochemical injury in mice
Journal of Thrombosis and Haemostasis, 2003Co-Authors: Katina M. Wilson, Cynthia M Lynch, Frank M Faraci, Steven R. LentzAbstract:Summary. Background: Increasing use of transgenic and gene targeting techniques for the investigation of hemostasis and vascular biology has generated interest in Experimental models of carotid artery Thrombosis in mice. Objectives: We tested the hypothesis that hypoventilation in anesthetized mice may cause hypercapnia, increased carotid artery blood flow, and altered thrombotic responses to photochemical injury of the carotid artery. Methods: Arterial blood gases and carotid artery blood flow were measured in pentobarbital-anesthetized BALB/c or C57BL/6 J mice with and without mechanical ventilation. Photochemical injury of the carotid artery was induced using the rose bengal method. Results: Compared with ventilated mice, unventilated mice had a 45% increase in carotid artery blood flow (0.74 ± 0.04 vs. 0.41 ± 0.03 mL min−1; P < 0.001) that was associated with an elevation of arterial PCO2 (58 ± 4 vs. 33 ± 4 mmHg; P < 0.05) and a decrease in arterial pH (7.18 ± 0.05 vs. 7.32 ± 0.03; P < 0.05). Time to first occlusion of the carotid artery after photochemical injury was shorter in ventilated than in unventilated mice (29 ± 6 vs. 73 ± 9 min; P < 0.001). Time to stable occlusion was also shorter in ventilated mice (49 ± 8 vs. 81 ± 6 min; P < 0.05). Elevated carotid artery blood flow, hypercarbic acidosis, and prolonged occlusion times also were observed in mice ventilated with supplemental carbon dioxide. Conclusions: General anesthesia without mechanical ventilation has the potential to confound studies of Experimental Thrombosis in vivo by producing hypoventilation, hypercapnia, acidosis, and altered carotid artery blood flow. Mechanical ventilation with maintenance of normal blood gases may enhance the physiological insight gained from Experimental models of carotid artery Thrombosis in mice.
J Ten W Cate - One of the best experts on this subject based on the ideXlab platform.
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comparison of sustained antithrombotic effects of inhibitors of thrombin and factor xa in Experimental Thrombosis
Circulation, 1996Co-Authors: B J Biemond, Philip W Friederich, M Levi, George P Vlasuk, H R Buller, J Ten W CateAbstract:Background In the pathogenesis of (recurrent) Thrombosis, clot-associated thrombin appears to play an important role. Antithrombin III–independent thrombin inhibitors have been shown to neutralize clot-bound thrombin effectively. We compared the sustained antithrombotic effects and the effects on endogenous fibrinolysis of several of these agents with recombinant tick anticoagulant peptide (rTAP), a selective factor Xa inhibitor, and low-molecular-weight heparin (LMWH) in an Experimental venous Thrombosis model. Methods and Results Rabbits received either recombinant hirudin (rHir), Hirulog-1, CVS#995 (a novel direct inhibitor of thrombin), rTAP, LMWH, or saline. The effect on thrombus growth was assessed by measuring the accretion of 125I-labeled fibrinogen onto preformed nonradioactive thrombi, and the effect on endogenous fibrinolysis was assessed by measuring the decline in radioactivity of preformed 125I-labeled thrombi in rabbit jugular veins. All direct thrombin inhibitors induced a sustained antit...
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inhibition of plasminogen activator inhibitor 1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of Experimental Thrombosis
Circulation, 1992Co-Authors: Marcel Levi, B J Biemond, J Ten W Cate, A J Van Zonneveld, Hans PannekoekAbstract:BACKGROUND We investigated the effect of inhibition of plasminogen activator inhibitor-1 (PAI-1) activity by a murine monoclonal anti-human PAI-1 antibody (MAI-12) on in vitro thrombolysis and on in vivo thrombolysis and thrombus extension in an Experimental animal model for Thrombosis. METHODS AND RESULTS Thrombolysis, mediated by recombinant tissue-type plasminogen activator (rt-PA), was studied in an in vitro system consisting of fibrinogen, plasminogen, and thrombin. Addition of purified platelets during clot formation inhibited rt-PA-mediated thrombolysis in a dose-dependent manner. Platelet-dependent thrombolysis resistance could be completely neutralized by the monoclonal antibody MAI-12, supporting the notion that the observed resistance is due to PAI-1 released from alpha-granules of platelets. Subsequently, we monitored in vivo thrombolysis and thrombus extension of human whole blood thrombi that were allowed to form in rabbit jugular veins. During thrombus formation, either MAI-12 or an irrelevant antibody was incorporated. Thrombolysis and thrombus extension were simultaneously measured during endogenous thrombolysis or upon administration of different dosages of rt-PA. We observed that endogenous thrombolysis was enhanced in the presence of MAI-12 compared with the control antibody. Significantly, thrombus extension was partially prevented by MAI-12 and not by the control antibody irrespective of whether exogenous rt-PA was systematically administered. CONCLUSIONS These observations further confirm the essential role of PAI-1 in the regulation of the thrombolytic system and support the exploration of adjunctive therapy based on inhibition of PAI-1 activity in thrombolytic strategies.
