Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice

Vicente, Cristina Pontes; He, Li; Pavão, Mauro S. G.; Tollefsen, Douglas M.

doi:10.1182/blood-2004-02-0598

Cited by 54 publications

(49 citation statements)

References 25 publications

(29 reference statements)

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“…12 We also demonstrated that dermatan sulfate inhibits thrombosis when administered intravenously to wild-type mice but has no effect in HCII-deficient mice. 16 These results established that HCII has antithrombotic activity in vivo and that its activity can be augmented by infusion of dermatan sulfate. In the current study, we compared atherogenesis and neointima formation in wild-type and HCII-deficient mice and investigated the effect of intravenous dermatan sulfate administration on neointima formation.…”

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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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“…The doses of dermatan sulfate and heparin chosen for these experiments were previously shown to have equivalent antithrombotic effects in wild-type mice, prolonging the thrombosis time of the carotid artery after photochemical injury from approximately 60 minutes to 100 minutes. 16 …”

Section: Dermatan Sulfate Inhibits Neointima Formation In Wild-type Micementioning

confidence: 99%

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

Vicente

Tollefsen

2007

Blood

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“…The carotid artery thrombosis was induced as described previously (21). Briefly, adult male and female rat (body weight, 200 g) were anesthetized with an intramuscular injection of 100 mg kg Ϫ1 of ketamine (Cristália, São Paulo, Brazil) and 16 mg kg Ϫ1 of xylazine (Bayer AS, São Paulo, Brazil), supplemented as needed, secured in the supine position, and placed under a dissecting microscope.…”

Section: Photochemically Induced Carotid Artery Lesionmentioning

confidence: 99%

Unique Extracellular Matrix Heparan Sulfate from the Bivalve Nodipecten nodosus (Linnaeus, 1758) Safely Inhibits Arterial Thrombosis after Photochemically Induced Endothelial Lesion

Gomes

Kozlowski

Pomin

et al. 2010

Journal of Biological Chemistry

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“…39 The CKD and sham animals were anesthetized with pentobarbital, secured in the supine position, and placed under a dissecting microscope. Following a midline cervical incision, the right common carotid artery was isolated, and we applied a Doppler flow probe (model 0.5 VB; Transonic Systems, Ithaca, New York).…”

Section: Photochemically Induced Carotid Artery Thrombosis In Micementioning

confidence: 99%

CKD Accelerates Development of Neointimal Hyperplasia in Arteriovenous Fistulas

Kokubo

Ishikawa

Uchida

et al. 2009

Journal of the American Society of Nephrology

106

100

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Arteriovenous (AV) access failure resulting from venous neointimal hyperplasia is a major cause of morbidity in patients with ESRD. To understand the role of chronic kidney disease (CKD) in the development of neointimal hyperplasia, we created AV fistulae (common carotid artery to jugular vein in an end-to-side anastomosis) in mice with or without CKD (renal ablation or sham operation). At 2 and 3 wk after operation, neointimal hyperplasia at the site of the AV anastomosis increased 2-fold in animals with CKD compared with controls, but cellular proliferation in the neointimal hyperplastic lesions did not significantly differ between the groups, suggesting that the enhanced neointimal hyperplasia in the setting of CKD may be secondary to a migratory phenotype of vascular smooth muscle cells (VSMC). In ex vivo migration assays, aortic VSMC harvested from mice with CKD migrated significantly greater than VSMC harvested from control mice. Moreover, animals with CKD had higher serum levels of osteopontin, which stimulates VSMC migration. When we treated animals with bone morphogenic protein-7, which promotes VSMC differentiation, before creation of the AV anastomosis, the effect of CKD on the development of neointimal hyperplasia was eliminated. In summary, CKD accelerates development of neointimal hyperplasia at the anastomotic site of an AV fistula, and administration of bone morphogenic protein-7 neutralizes this effect.

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Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice

Cited by 54 publications

References 25 publications

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

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

Unique Extracellular Matrix Heparan Sulfate from the Bivalve Nodipecten nodosus (Linnaeus, 1758) Safely Inhibits Arterial Thrombosis after Photochemically Induced Endothelial Lesion

CKD Accelerates Development of Neointimal Hyperplasia in Arteriovenous Fistulas

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