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(+)LRP(flox/flox)). Upon inactivation of the LRP gene, MX1cre(+)LRP(flox/flox) mice had significantly higher plasma FVIII as compared with control LRP(flox/flox) mice (3.4 and 2.0 U/mL, respectively; P <.001). Elevated plasma FVIII levels in MX1cre(+)LRP(flox/flox) mice coincided with increased plasma von Willebrand factor (VWF) (2.0 and 1.6 U/mL for MX1cre(+)LRP(flox/flox) and control LRP(flox/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(+)LRP(flox/flox) mice as compared with control LRP(flox/flox) mice. Administration of either a vasopressin analog or an endotoxin resulted in increased plasma VWF, but not FVIII. In clearance experiments, MX1cre(+)LRP(flox/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(+)LRP(flox/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.
authors.affiliation: Department of Plasma Proteins, Sanquin Research at CLB, Amsterdam, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Bovenschen
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Jos M
authors.initials: JM
authors.lastname: Grimbergen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Koen
authors.initials: K
authors.lastname: Mertens
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: van Vlijmen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D005169:Factor VIII / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D007700:Kinetics; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D026561:Low Density Lipoprotein Receptor-Related Protein-2; D014841:von Willebrand Factor; D005169:Factor VIII