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

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

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

It has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP-deficient mice (MX1cre+LRPflox/flox). Upon inactivation of the LRP gene, MX1cre+-LRPflox/flox mice had significantly higher plasma FVIII as compared with control LRPflox/flox mice (3.4 and 2.0 U/mL, respectively; P < .001). Elevated plasma FVIII levels in MX1cre+LRPflox/flox mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre+LRPflox/flox and control LRPflox/flox mice, respectively; P < .05). Elevation of plasma FVIII and VWF persisted for at least 6 weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and VWF in individual mice, we observed an increase of the FVIII/VWF ratio in MX1cre+LRPflox/flox mice as compared with control LRPflox/flox mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre+LRPflox/flox mice displayed a 1.5-fold prolongation of FVIII mean residence time. Adenovirus-mediated overexpression of the 39-kDa receptor-associated protein (RAP) in normal mice resulted in a 3.5-fold increase of plasma FVIII. These data confirm that the regulation of plasma FVIII in vivo involves a RAP-sensitive mechanism. Surprisingly, plasma FVIII in MX1cre+LRPflox/flox mice increased 2-fold after RAP gene transfer. We propose that RAP-sensitive determinants other than hepatic LRP contribute to the regulation of plasma FVIII in vivo.

Original languageEnglish (US)
Pages (from-to)3933-3939
Number of pages7
JournalBlood
Volume101
Issue number10
DOIs
StatePublished - May 15 2003

Fingerprint

LDL-Receptor Related Proteins
Protein Deficiency
LDL Receptors
Factor VIII
Plasmas
Lipoprotein Receptors
Proteins
von Willebrand Factor
LDL-Receptor Related Protein-Associated Protein
Gene transfer
Vasopressins
Adenoviridae
Endotoxins

ASJC Scopus subject areas

  • Hematology

Cite this

Bovenschen, N., Herz, J., Grimbergen, J. M., Lenting, P. J., Havekes, L. M., Mertens, K., & Van Vlijmen, B. J. M. (2003). Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. Blood, 101(10), 3933-3939. https://doi.org/10.1182/blood-2002-07-2081

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. / Bovenschen, Niels; Herz, Joachim; Grimbergen, Jos M.; Lenting, Peter J.; Havekes, Louis M.; Mertens, Koen; Van Vlijmen, Bart J M.

In: Blood, Vol. 101, No. 10, 15.05.2003, p. 3933-3939.

Research output: Contribution to journalArticle

Bovenschen, N, Herz, J, Grimbergen, JM, Lenting, PJ, Havekes, LM, Mertens, K & Van Vlijmen, BJM 2003, 'Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency', Blood, vol. 101, no. 10, pp. 3933-3939. https://doi.org/10.1182/blood-2002-07-2081
Bovenschen, Niels ; Herz, Joachim ; Grimbergen, Jos M. ; Lenting, Peter J. ; Havekes, Louis M. ; Mertens, Koen ; Van Vlijmen, Bart J M. / Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency. In: Blood. 2003 ; Vol. 101, No. 10. pp. 3933-3939.
@article{c8c41b96f17e4b62988dc6b003e3d394,
title = "Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency",
abstract = "It has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP-deficient mice (MX1cre+LRPflox/flox). Upon inactivation of the LRP gene, MX1cre+-LRPflox/flox mice had significantly higher plasma FVIII as compared with control LRPflox/flox mice (3.4 and 2.0 U/mL, respectively; P < .001). Elevated plasma FVIII levels in MX1cre+LRPflox/flox mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre+LRPflox/flox and control LRPflox/flox mice, respectively; P < .05). Elevation of plasma FVIII and VWF persisted for at least 6 weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and VWF in individual mice, we observed an increase of the FVIII/VWF ratio in MX1cre+LRPflox/flox mice as compared with control LRPflox/flox mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre+LRPflox/flox mice displayed a 1.5-fold prolongation of FVIII mean residence time. Adenovirus-mediated overexpression of the 39-kDa receptor-associated protein (RAP) in normal mice resulted in a 3.5-fold increase of plasma FVIII. These data confirm that the regulation of plasma FVIII in vivo involves a RAP-sensitive mechanism. Surprisingly, plasma FVIII in MX1cre+LRPflox/flox mice increased 2-fold after RAP gene transfer. We propose that RAP-sensitive determinants other than hepatic LRP contribute to the regulation of plasma FVIII in vivo.",
author = "Niels Bovenschen and Joachim Herz and Grimbergen, {Jos M.} and Lenting, {Peter J.} and Havekes, {Louis M.} and Koen Mertens and {Van Vlijmen}, {Bart J M}",
year = "2003",
month = "5",
day = "15",
doi = "10.1182/blood-2002-07-2081",
language = "English (US)",
volume = "101",
pages = "3933--3939",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "10",

}

TY - JOUR

T1 - Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency

AU - Bovenschen, Niels

AU - Herz, Joachim

AU - Grimbergen, Jos M.

AU - Lenting, Peter J.

AU - Havekes, Louis M.

AU - Mertens, Koen

AU - Van Vlijmen, Bart J M

PY - 2003/5/15

Y1 - 2003/5/15

N2 - It has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP-deficient mice (MX1cre+LRPflox/flox). Upon inactivation of the LRP gene, MX1cre+-LRPflox/flox mice had significantly higher plasma FVIII as compared with control LRPflox/flox mice (3.4 and 2.0 U/mL, respectively; P < .001). Elevated plasma FVIII levels in MX1cre+LRPflox/flox mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre+LRPflox/flox and control LRPflox/flox mice, respectively; P < .05). Elevation of plasma FVIII and VWF persisted for at least 6 weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and VWF in individual mice, we observed an increase of the FVIII/VWF ratio in MX1cre+LRPflox/flox mice as compared with control LRPflox/flox mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre+LRPflox/flox mice displayed a 1.5-fold prolongation of FVIII mean residence time. Adenovirus-mediated overexpression of the 39-kDa receptor-associated protein (RAP) in normal mice resulted in a 3.5-fold increase of plasma FVIII. These data confirm that the regulation of plasma FVIII in vivo involves a RAP-sensitive mechanism. Surprisingly, plasma FVIII in MX1cre+LRPflox/flox mice increased 2-fold after RAP gene transfer. We propose that RAP-sensitive determinants other than hepatic LRP contribute to the regulation of plasma FVIII in vivo.

AB - It has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP-deficient mice (MX1cre+LRPflox/flox). Upon inactivation of the LRP gene, MX1cre+-LRPflox/flox mice had significantly higher plasma FVIII as compared with control LRPflox/flox mice (3.4 and 2.0 U/mL, respectively; P < .001). Elevated plasma FVIII levels in MX1cre+LRPflox/flox mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre+LRPflox/flox and control LRPflox/flox mice, respectively; P < .05). Elevation of plasma FVIII and VWF persisted for at least 6 weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and VWF in individual mice, we observed an increase of the FVIII/VWF ratio in MX1cre+LRPflox/flox mice as compared with control LRPflox/flox mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre+LRPflox/flox mice displayed a 1.5-fold prolongation of FVIII mean residence time. Adenovirus-mediated overexpression of the 39-kDa receptor-associated protein (RAP) in normal mice resulted in a 3.5-fold increase of plasma FVIII. These data confirm that the regulation of plasma FVIII in vivo involves a RAP-sensitive mechanism. Surprisingly, plasma FVIII in MX1cre+LRPflox/flox mice increased 2-fold after RAP gene transfer. We propose that RAP-sensitive determinants other than hepatic LRP contribute to the regulation of plasma FVIII in vivo.

UR - http://www.scopus.com/inward/record.url?scp=0037926885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037926885&partnerID=8YFLogxK

U2 - 10.1182/blood-2002-07-2081

DO - 10.1182/blood-2002-07-2081

M3 - Article

VL - 101

SP - 3933

EP - 3939

JO - Blood

JF - Blood

SN - 0006-4971

IS - 10

ER -