Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Bovenschen, Niels; Herz, Joachim; Grimbergen, Jos; Lenting, Peter J.; Havekes, Louis M.; Mertens, Koen; Vlijmen, Bart J.M. van

doi:10.1182/blood-2002-07-2081

Cited by 110 publications

(149 citation statements)

References 53 publications

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“…125 I]FVIII in mice, most of the radioactivity was accumulated in the liver (5), which further supports the role of LDLR in the above study (6).…”

Section: Discussionsupporting

confidence: 72%

“…In LRP-deficient mice, adenovirus-mediated overexpression of RAP resulted in an increase of FVIII level (6). Most likely, this was due to blocking of LDLR by RAP, and not other RAP-sensitive determinants.…”

Section: Discussionmentioning

confidence: 97%

“…Indeed, deficiency in either LDLR or LRP in mice prolonged the half-life of FVIII about 1.5-fold, whereas the combined deficiency resulted in ϳ4.8-fold prolongation (2). Furthermore, inhibition of both receptors by their highly specific ligand ␣-2-macroglobulin receptor-associated protein (RAP) (3,4) increased its half-life in mice (5,6). In humans, polymorphism in either LDLR or LRP is associated with elevated levels of FVIII (7)(8)(9)(10).…”

Section: Factor VIII (Fviii)mentioning

confidence: 99%

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Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

Kurasawa

Shestopal

Karnaukhova

et al. 2013

Journal of Biological Chemistry

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Background: Low density lipoprotein receptor (LDLR) mediates clearance of blood coagulation factor VIII (FVIII). Results:The region of complement-type repeats 2-5 in LDLR was identified as the binding site for FVIII and for ␣-2-macroglobulin receptor-associated protein (RAP). Conclusion: Binding sites of LDLR for FVIII, and also for RAP, were characterized. Significance: This provides new data on LDLR structure and function and on FVIII catabolism.

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“…125 I]FVIII in mice, most of the radioactivity was accumulated in the liver (5), which further supports the role of LDLR in the above study (6).…”

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 97%

Section: Factor VIII (Fviii)mentioning

confidence: 99%

See 1 more Smart Citation

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

Kurasawa

Shestopal

Karnaukhova

et al. 2013

Journal of Biological Chemistry

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“…15 FVIII activity, von Willeband factor (VWF) antigen, and t-PA antigen were determined in citrated plasma. 16,17 …”

Section: Plasma Parametersmentioning

confidence: 99%

Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Santo

Pires

Boesten

et al. 2004

Blood

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“…23,26,53 In addition, LRP1 has been shown to bind to VWF in a shear-dependent manner. Importantly, Rastegarlari et al previously demonstrated that the inhibitory effects of RAP on VWF clearance were predominantly modulated through macrophage LRP1 rather than LRP1 (A) A model of the VWF A2 domain was prepared as previously described.…”

Section: Glycan Structures At N1515 and N1574 In The A2 Domain Influementioning

confidence: 99%

N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

Chion

O’Sullivan

Drakeford

et al. 2016

Blood

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Key Points• The A1 domain of VWF contains a cryptic binding site that plays a key role in regulating macrophage binding and clearance.• The N-linked glycans presented at N1515 and N1574 within the A2 domain of VWF modulate macrophage-mediated clearance.Enhanced von Willebrand factor (VWF) clearance is important in the etiology of von Willebrand disease. However, the molecular mechanisms underlying VWF clearance remain poorly understood. In this study, we investigated the role of VWF domains and specific glycan moieties in regulating in vivo clearance. Our findings demonstrate that the A1 domain of VWF contains a receptor-recognition site that plays a key role in regulating the interaction of VWF with macrophages. In A1-A2-A3 and full-length VWF, this macrophage-binding site is cryptic but becomes exposed following exposure to shear or ristocetin. Previous studies have demonstrated that the N-linked glycans within the A2 domain play an important role in modulating susceptibility to ADAMTS13 proteolysis. We further demonstrate that these glycans presented at N1515 and N1574 also play a critical role in protecting VWF against macrophage binding and clearance. Indeed, loss of the N-glycan at N1515 resulted in markedly enhanced VWF clearance that was significantly faster than that observed with any previously described VWF mutations. In addition, A1-A2-A3 fragments containing the N1515Q or N1574Q substitutions also demonstrated significantly enhanced clearance. Importantly, clodronate-induced macrophage depletion significantly attenuated the increased clearance observed with N1515Q and N1574Q in both full-length VWF and A1-A2-A3.Finally, we further demonstrate that loss of these N-linked glycans does not enhance clearance in VWF in the presence of a structurally constrained A2 domain. Collectively, these novel findings support the hypothesis that conformation of the VWF A domains plays a critical role in modulating macrophage-mediated clearance of VWF in vivo. (Blood. 2016;128(15):1959-1968

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Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Cited by 110 publications

References 53 publications

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

Mapping the Binding Region on the Low Density Lipoprotein Receptor for Blood Coagulation Factor VIII

Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

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