von Willebrand factor arginine 1205 substitution results in accelerated macrophage-dependent clearance in vivo
von Willebrand factor arginine 1205 substitution results in accelerated macrophage-dependent clearance in vivo
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DOI：
10.1111/jth.12875
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发表时间：
2015-05-01
影响因子：
10.4
通讯作者：
O'Donnell, J. S.
中科院分区：
文献类型：
--
作者：
Rawley, O.;O'Sullivan, J. M.;O'Donnell, J. S.
背景：血管性血友病因子（VWF）清除增强在1型和2型血管性血友病（VWD）的病因学中很重要。在清除率增强的患者中已经报道了20多种不同的VWF点突变。其中包括VWD-Vicenza变体，其特征是在VWF D3结构域中有Arg1205His取代。然而，关键的是，VWF中单氨基酸取代导致这种复杂的多聚糖蛋白清除增强的分子机制尚未确定。目的在本研究中，我们探讨了VWF-R1205H变异增强清除的生物学基础。方法用VWF-/-小鼠，测定了一系列全长和截短的重组VWF变体的体内清除率。此外，巨噬细胞在调节增强VWD-Vicenza清除中的作用通过氯钠脂质体进行了研究。结果用组氨酸、半胱氨酸或丝氨酸替代R1205均可显著降低全长重组VWF的存活率。重要的是，含有相同R1205替换的D'A3片段也显示出显著增强的清除率。与R1205H降低体内生存相比，R1204H的清除率没有增强。最近的研究表明，肝和脾巨噬细胞在调节VWF清除中起关键作用。重要的是，巨噬细胞消耗也有助于显著减弱与VWF-R1205H、VWF-R1205S和VWF-R1205C相关的增强清除表型。总之，这些新发现证明了R1205残基在调节巨噬细胞介导的VWFin体内清除中具有特定的关键作用。
BackgroundEnhanced von Willebrand factor (VWF) clearance is important in the etiology of type 1 and type 2 von Willebrand disease (VWD). More than 20 different VWF point mutations have already been reported in patients with enhanced clearance. These include the VWD-Vicenza variant, which is characterized by an Arg1205His substitution in the VWF D3 domain. Critically, however, the molecular mechanisms through which single amino acid substitutions in VWF result in enhanced clearance of this complex multimeric glycoprotein have not been defined.ObjectivesIn this study, we have investigated the biological basis underlying the enhanced clearance of the VWF-R1205H variant.MethodsUsing VWF-/- mice, in vivo clearance rates were determined for a series of full-length and truncated recombinant VWF variants. In addition, the role of macrophages in modulating enhanced VWD-Vicenza clearance was investigated using clodronate liposome administration.ResultsOur findings demonstrate that substitutions of R1205 with histidine, cysteine or serine all result in markedly reduced survival of full-length recombinant VWF. Importantly, D'A3 fragments containing these same R1205 substitutions also demonstrated significantly enhanced clearance. In contrast to the reduced in vivo survival observed with R1205H, clearance of R1204H was not enhanced. Recent studies have demonstrated that hepatic and splenic macrophages play key roles in regulating VWF clearance. Importantly, macrophage-depletion also served to markedly attenuate the enhanced clearance phenotypes associated with VWF-R1205H, VWF-R1205S and VWF-R1205C.ConclusionsCollectively, these novel findings demonstrate a specific and critical role for the R1205 residue in modulating macrophage-mediated clearance of VWFin vivo.