| Title: |
In vivo clearance of human protein S in a mouse model - Influence of c4b-binding protein and the Heerlen polymorphism |
| Authors: |
Denis, CV; Roberts, SJ; Hackeng, TM; Lenting, PJ |
| Source: |
Denis, CV, Roberts, SJ, Hackeng, TM & Lenting, PJ 2005, 'In vivo clearance of human protein S in a mouse model - Influence of c4b-binding protein and the Heerlen polymorphism', Arteriosclerosis Thrombosis and Vascular Biology, vol. 25, no. 10, pp. 2209-2215. https://doi.org/10.1161/01.ATV.0000181760.55269.6b |
| Publication Year: |
2005 |
| Collection: |
Maastricht University Research Publications |
| Subject Terms: |
protein S; C4b-binding; clearance; FACTOR-VA; ENDOTHELIAL-CELLS; COFACTOR ACTIVITY; APOPTOTIC CELLS; APC-COFACTOR; FACTOR-VIII; SER 460; DEFICIENCY; BINDING; INACTIVATION |
| Description: |
Objective - To explore the effect of the Heerlen polymorphism and C4b-binding protein (C4BP) on protein S catabolism in vitro and in vivo. Methods and Results - Radiolabeled protein S was efficiently bound and intracellularly degraded by THP-1 macrophages, and both processes were strongly reduced in the presence of the protein S-carrier protein C4BP. To test whether C4BP displays a similar protective effect in vivo, survival experiments were performed in mice. In the absence of C4BP, radiolabeled human protein S disappeared in a biphasic manner ( mean residence time [MRT] 2 hours). However, the presence of C4BP resulted in a 4-fold prolonged survival of protein S ( MRT 8 hours; P < 0.0001). We also applied this experimental model to recombinant protein S-Heerlen, a naturally occurring variant that contains a Ser460Pro substitution. These clearance experiments revealed a strongly decreased survival of recombinant protein S-S460P ( MRT 0.6 hours; P = 0.021), which could be compensated partially by C4BP ( MRT 1.4 hours; P = 0.012 compared with protein S-S460P). Conclusion - Protein S-S460P has a reduced survival in vivo, which may explain the low levels of free protein S in individuals carrying this polymorphism. Furthermore, C4BP prevents premature clearance of protein S and uses this ability to compensate the increased clearance of protein S-S460P. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
1079-5642; 1524-4636 |
| Relation: |
info:eu-repo/semantics/altIdentifier/wos/000232231500030; info:eu-repo/semantics/altIdentifier/pissn/1079-5642; info:eu-repo/semantics/altIdentifier/eissn/1524-4636 |
| DOI: |
10.1161/01.ATV.0000181760.55269.6b |
| Availability: |
https://cris.maastrichtuniversity.nl/en/publications/cf459065-5685-4bdb-98d9-b475e6df53f6; https://doi.org/10.1161/01.ATV.0000181760.55269.6b |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.FE8D1793 |
| Database: |
BASE |