Comparative metabolism and distribution of rabbit heparin cofactor II and rabbit antithrombin in rabbits

Hatton, M. W. C.; Hoogendoorn, Hugh; Southward, Suzanne M.R.; Ross, Bonnie; Blajchman, Morris A.

doi:10.1152/ajpendo.1997.272.5.e824

Cited by 8 publications

(15 citation statements)

References 21 publications

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“…The apparent discrepancy between the results of these 2 studies may reflect differences in study design (prospective vs crosssectional), the age or ethnic background of the subjects, the clinical end point (symptomatic coronary heart disease vs carotid atherosclerosis), or the assay method (activity vs antigen). Furthermore, studies on the distribution of radiolabeled HCII in humans 28 or rabbits 29 suggest that 40% to 60% of the HCII equilibrates into compartments outside the bloodstream. Thus, the plasma HCII concentration may not reflect the total amount of HCII present in specific vascular beds.…”

Section: Discussionmentioning

confidence: 99%

Accelerated atherogenesis and neointima formation in heparin cofactor II–deficient mice

Vicente

Tollefsen

2007

Blood

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Heparin cofactor II (HCII) is a plasma protein that inhibits thrombin when bound to dermatan sulfate or heparin. HCIIdeficient mice are viable and fertile but rapidly develop thrombosis of the carotid artery after endothelial injury. We now report the effects of HCII deficiency on atherogenesis and neointima formation. HCII-null or wild-type mice, both on an apolipoprotein E-null background, were fed an atherogenic diet for 12 weeks. HCII-null mice developed plaque areas in the aortic arch approximately 64% larger than wild-type mice despite having similar plasma lipid and glucose levels. Neointima formation was induced by mechanical dilation of the common carotid artery. Thrombin activity, determined by hirudin binding or chromogenic substrate hydrolysis within 1 hour after injury, was higher in the arterial walls of HCII-null mice than in wild-type mice. After 3 weeks, the median neointimal area was 2-to 3-fold greater in HCII-null than in wild-type mice. Dermatan sulfate administered intravenously within 48 hours after injury inhibited neointima formation in wild-type mice but had no effect in HCII-null mice. Heparin did not inhibit neointima formation. We conclude that HCII deficiency promotes atherogenesis and neointima formation and that treatment with dermatan sulfate reduces neointima formation in an HCII-dependent manner. IntroductionThrombin may participate in formation of atherosclerotic plaques and stimulate proliferation of arterial smooth muscle cells following angioplasty and stent placement. Disruption of the endothelium or the fibrous cap of an atherosclerotic plaque during angioplasty exposes plasma factor VIIa to tissue factor in the arterial wall. 1,2 The factor VIIa/tissue factor complex then converts factor X to factor Xa, which in combination with factor Va converts prothrombin to thrombin. Thrombin converts fibrinogen to fibrin monomers, which polymerize to form a clot, and stimulates platelet aggregation and degranulation by cleaving G-protein-coupled protease activated receptors (specifically, PAR1 and PAR4) on the platelet membrane. 3 The earliest histologic response to stent placement includes local deposition of fibrin and platelets, providing good evidence for thrombin generation in this setting. 4 Thrombin can also activate PAR1 on nearby endothelial cells. 3 In response, the endothelial cells express adhesion molecules and release a variety of mediators that recruit platelets and leukocytes. Therefore, thrombin could play a role in the infiltration of neutrophils, lymphocytes, and macrophages that occurs during the first few days after stent placement. Over the next 2 to 4 weeks, the fibrin and platelets disappear, and restenosis may occur as a result of proliferation of smooth muscle cells and deposition of extracellular matrix in the neointima. 4 Thrombin may induce smooth muscle cell proliferation directly, by activation of PAR1 on these cells, or indirectly, by causing platelets to secrete platelet-derived growth factor.Several of these thrombin-dependent events, including st...

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Section: Discussionmentioning

confidence: 99%

Accelerated atherogenesis and neointima formation in heparin cofactor II–deficient mice

Vicente

Tollefsen

2007

Blood

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Section: Discussionmentioning

confidence: 77%

“…Other investigators have reported, however, that HCII is present in the intima of normal human arteries 42 and that radiolabeled HCII is taken up into the intima or media of the intact rabbit aorta. 37 Nevertheless, it is clear from our immunohistochemical experiments that much larger amounts of HCII enter the arterial wall following endothelial injury.The results of this study support a model in which HCII becomes activated by binding to DS in the arterial wall after disruption of the endothelium. This model is consistent with the observation that HCII Ϫ/Ϫ mice do not show signs of spontaneous thrombosis but develop thrombi more rapidly than wild-type mice after arterial injury 14 ; furthermore, the ability of recombinant HCII to restore the thrombosis time of HCII Ϫ/Ϫ mice to normal correlates with its ability to bind to DS in the arterial adventitia.…”

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confidence: 77%

“…[37][38][39] Although HCII levels have not been measured in interstitial fluid, lymph collected from rabbit hind limbs contains other hemostatic proteins at substantial concentrations, which are roughly in inverse proportion to the proteins' molecular weights. 40 Since AT, which is similar to HCII in molecular weight, is present in hind limb lymph at approximately 40% of its plasma concentration, it is likely that HCII would also be found in lymph.…”

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confidence: 99%

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Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II

He¹,

Giri

Vicente

et al. 2008

Blood

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Heparin cofactor II (HCII)-deficient mice form occlusive thrombi more rapidly than do wild-type mice following injury to the carotid arterial endothelium. Dermatan sulfate (DS) and heparan sulfate (HS) increase the rate of inhibition of thrombin by HCII in vitro, but it is unknown whether vascular glycosaminoglycans play a role in the antithrombotic effect of HCII in vivo. In this study, we found that intravenous injection of either wild-type recombinant HCII or a variant with low affinity for HS (K173H) corrected the abnormally short thrombosis time of HCII-deficient mice, while a variant with low affinity for DS (R189H) had no effect. When HCII was incubated with frozen sections of the mouse carotid artery, it bound specifically to DS in the adventitia. HCII was undetectable in the wall of the uninjured carotid artery, but it became concentrated in the adventitia following endothelial injury. These results support the hypothesis that HCII interacts with DS in the vessel wall after disruption of the endothelium and that this interaction regulates thrombus formation in vivo. IntroductionVascular injury allows circulating coagulation factor VIIa to interact with tissue factor. 1 This interaction triggers a series of zymogen activation reactions, which lead to generation of the proteolytic enzyme thrombin. Thrombin promotes clot formation by converting fibrinogen to fibrin, by stimulating platelet aggregation and secretion, and by activating certain proteins (factors V, VIII, and XI) upstream in the coagulation cascade. Thrombin also has multiple effects on vascular endothelial cells, smooth muscle cells, and monocytes/macrophages that may be important in tissue repair or in the development of atherosclerotic or neointimal lesions. 2 Thrombin can be inhibited by 2 serpins, antithrombin (AT) and heparin cofactor II (HCII), which are produced by the liver and circulate at micromolar concentrations in plasma. 3 Both of these serpins inhibit thrombin at least 1000 times faster upon interaction with certain glycosaminoglycans. AT is activated by heparin or by heparan sulfate (HS) proteoglycans synthesized by vascular endothelial cells and is thought to produce an antithrombotic effect at the blood-endothelial interface. 4 Patients with partial AT deficiency have an increased incidence of venous thromboembolism, 5 and homozygous AT-deficient mice die in late gestation with evidence of fibrin deposition and a consumptive coagulopathy. 6 Heparin and HS also bind and activate HCII, although with much lower affinity in comparison with AT. 7 By contrast, purified dermatan sulfate (DS), 7 as well as DS proteoglycans synthesized by fibroblasts, 8,9 stimulate thrombin inhibition by HCII but not by AT; these findings support the hypothesis that HCII inhibits thrombin in the vessel wall after disruption of the endothelium. Patients with low plasma concentrations of HCII do not appear to be at increased risk for venous thrombosis, 10 but they may be predisposed to development of atherosclerosis 11 or neointima formation following...

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“…GAGs, commonly heparin but also DS, are used clinically for both prophylaxis and treatment of thrombosis (34,35). The disadvantages of these GAGs, to differing degrees, include risk of bleeding (35)(36)(37)(38), resistance of clot bound thrombin, short intravenous halflife compared with the plasma protein inhibitors (antithrombin and HC), whose action they catalyze (24,25,39), and decreased activity due to binding to proteins in vivo (14,20,23). We have produced and investigated the properties of two HC-GAG covalent complexes (HCH and HCD), which have a number of desirable properties that suggest they may have clinical applications related to selective thrombin inhibition.…”

Section: Discussionmentioning

confidence: 99%

Covalent Heparin Cofactor II-Heparin and Heparin Cofactor II-Dermatan Sulfate Complexes

Monagle¹,

Berry²,

O’Brodovich³

et al. 1998

Journal of Biological Chemistry

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Heparin cofactor II is a naturally occurring anticoagulant that acts by specifically inhibiting thrombin and is facilitated by the binding of glycosaminoglycans such as heparin and dermatan sulfate. In vivo, heparin cofactor II-glycosaminoglycan complexes dissociate, leaving the inhibitor less active in its ability to function as a component of the anticoagulation pathway. We have produced permanently activated heparin cofactor II molecules by covalent linkage to either heparin or dermatan sulfate. Covalent heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate complexes had catalytic antithrombin activities similar to those of the corresponding starting heparin and dermatan sulfate (86% and 110% of standard heparin and dermatan sulfate activity, respectively). Both heparin cofactor II-heparin and heparin cofactor II-dermatan sulfate had fast bimolecular rate constants of 1.4 ؋ 10 7 M ؊1 s ؊1 and 1.3 ؋ 10 7 M ؊1 s ؊1 , respectively, for reaction with thrombin. The intravenous half-life of the covalent complexes in rabbits was significantly longer than that of free heparin or dermatan sulfate (4.4, 3.4, 0.33, and 0.50 h for heparin cofactor II-heparin, heparin cofactor II-dermatan sulfate, heparin, and dermatan sulfate, respectively). Given their unique properties, these conjugates may have a clinical application for long term, selective inhibition of thrombin.

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Comparative metabolism and distribution of rabbit heparin cofactor II and rabbit antithrombin in rabbits

Cited by 8 publications

References 21 publications

Accelerated atherogenesis and neointima formation in heparin cofactor II–deficient mice

Accelerated atherogenesis and neointima formation in heparin cofactor II–deficient mice

Vascular dermatan sulfate regulates the antithrombotic activity of heparin cofactor II

Covalent Heparin Cofactor II-Heparin and Heparin Cofactor II-Dermatan Sulfate Complexes

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