Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency
Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor-related protein deficiency
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DOI：
10.1182/blood-2002-07-2081
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发表时间：
2003-05-15
期刊：
影响因子：
20.3
通讯作者：
van Viijmen, BJM
中科院分区：
文献类型：
--
作者：
Bovenschen, N;Herz, J;van Viijmen, BJM
低密度脂蛋白受体相关蛋白(LRP)在体外参与了细胞对凝血因子VIII(FVIII)的摄取和降解。为了探讨LIRP在体内调节血浆FVIII的生理学作用，我们使用了cre/loxP介导的条件性LRP缺陷小鼠(MX1cre(+)LRP(FLOX/FLOX))。在LIRP基因失活后，MX1cre(+)-LRPflx/FLOX小鼠的血浆FVIII水平显著高于对照LRPFLOX/FLOX小鼠(分别为3.4和2.0U/mL；P<；.001)。MX1cre(+)LRP(FLOX/FLOX)小鼠血浆FVIII水平升高与血浆von Wille-Brand因子(VWF)升高一致(MX1cre(+)LRP(FLOX/FLOX)小鼠和对照LRPFLOX/FLOX小鼠分别为2.0和1.6U/mL；P<；0.05)。在LRP基因失活后，血浆FVIII和VWF的升高持续了至少6周。通过比较单个小鼠的血浆FVIII和VWF，我们观察到MX1cre(+)LRP(FLOX/FLOX)小鼠与对照LRPFLOX/FLOX小鼠相比，FVIII/VWF比值升高。给予加压素类似物或内毒素均可导致血浆VWF升高，但不会导致FVIII升高。在清除实验中，MX1cre(+)LRP(FLOX/FLOX)小鼠的FVIII平均停留时间延长了1.5倍。腺病毒介导的39 kDa受体相关蛋白(RAP)在正常小鼠中的过度表达导致血浆FVIII增加3.5倍。这些数据证实，体内血浆FVIII的调节涉及一种RAP敏感机制。令人惊讶的是，在RAP基因转移后，MX1cre(+)LRP(FLOX/FLOX)小鼠的血浆FVIII增加了2倍。我们认为，在体内，RAP敏感决定因素而不是肝脏LRP参与了对血浆FVIII的调节。(C)2003年，由美国血液病学会提供。
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 LIRP in regulating plasma FVIII in vivo, we used cre/loxP-mediated conditional LRP-deficient mice (MX1cre(+)LRP(flox/flox)). Upon inactivation of the LIRP 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(+)LRP(flox/flox) mice coincided with increased plasma von Wille-brand factor (VWF) (2.0 and 1.6 U/mL for MX1cre(+)LRP(flox/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(+)LRP(flox/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(+)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. (C) 2003 by The American Society of Hematology.