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Prepublished online as a Blood First Edition Paper on January 9, 2003; DOI 10.1182/blood-2002-07-2081. This Article Full Text (PDF) All Versions of this Article: 2002-07-2081v1 101/10/3933    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bovenschen, N. Articles by van Vlijmen, B. J M Search for Related Content PubMed PubMed Citation Articles by Bovenschen, N. Articles by van Vlijmen, B. J M Social Bookmarking                   What's this? Submitted July 15, 2002 Accepted December 30, 2002 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*, and Bart J M van Vlijmen Department of Plasma Proteins, Sanquin Research at CLB, Amsterdam, The Netherlands Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA Department of Gaubius Laboratory, TNO Prevention and Health, Leiden, The Netherlands Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands * Corresponding author; email: kmertens{at}sanquin.nl. 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 physiological role of LRP in regulating plasma FVIII in vivo, we have 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 to control LRPflox/flox mice (3.4 and 2.0 U/mL, respectively; P < 0.001). 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 < 0.05). Elevation of plasma FVIII and vWF persisted for at least six weeks after inactivation of the LRP gene. Upon comparing plasma FVIII and vWF within individual mice, an increase of FVIII/vWF ratio in MX1cre+LRPflox/flox mice was observed as compared to control LRPflox/flox mice. Administration of either a vasopressin analogue or 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 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 receptor-associated protein gene transfer. Collectively, we propose that other RAP-sensitive determinants than hepatic LRP contribute to the regulation of plasma FVIII in vivo. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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