Article ; Online: LDL receptor-related protein 1 contributes to the clearance of the activated factor VII-antithrombin complex.
Journal of thrombosis and haemostasis : JTH
2016 Volume 14, Issue 12, Page(s) 2458–2470
Abstract: Essentials Factor VIIa is cleared principally as a complex with antithrombin. Enzyme/serpin complexes are preferred ligands for the scavenger-receptor LRP1. Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1. Macrophage-expressed ... ...
| Abstract | Essentials Factor VIIa is cleared principally as a complex with antithrombin. Enzyme/serpin complexes are preferred ligands for the scavenger-receptor LRP1. Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1. Macrophage-expressed LRP1 contributes to the clearance of factor VIIa/antithrombin. Summary: Background Recent findings point to activated factor VII (FVIIa) being cleared predominantly (± 65% of the injected protein) as part of a complex with the serpin antithrombin. FVIIa-antithrombin complexes are targeted to hepatocytes and liver macrophages. Both cells lines abundantly express LDL receptor-related protein 1 (LRP1), a scavenger receptor mediating the clearance of protease-serpin complexes. Objectives To investigate whether FVIIa-antithrombin is a ligand for LRP1. Methods Binding of FVIIa and pre-formed FVIIa-antithrombin to purified LRP1 Fc-tagged cluster IV (rLRP1-cIV/Fc) and to human and murine macrophages was analyzed. FVIIa clearance was determined in macrophage LRP1 (macLRP1)-deficient mice. Results Solid-phase binding assays showed that FVIIa-antithrombin bound in a specific, dose-dependent and saturable manner to rLRP1-cIV/Fc. Competition experiments with human THP1 macrophages indicated that binding of FVIIa but not of FVIIa-antithrombin was reduced in the presence of annexin-V or anti-tissue factor antibodies, whereas binding of FVIIa-antithrombin but not FVIIa was inhibited by the LRP1-antagonist GST-RAP. Additional experiments revealed binding of both FVIIa and FVIIa-antithrombin to murine control macrophages. In contrast, no binding of FVIIa-antithrombin to macrophages derived from macLRP1-deficient mice could be detected. Clearance of FVIIa-antithrombin but not of active site-blocked FVIIa was delayed 1.5-fold (mean residence time of 3.3 ± 0.1 h versus 2.4 ± 0.2 h) in macLRP1-deficient mice. The circulatory presence of FVIIa was prolonged to a similar extent in macLRP1-deficient mice and in control mice. Conclusions Our data show that FVIIa-antithrombin but not FVIIa is a ligand for LRP1, and that LRP1 contributes to the clearance of FVIIa-antithrombin in vivo. |
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| MeSH term(s) | Animals ; Antithrombins/metabolism ; Carrier Proteins/metabolism ; Catalytic Domain ; Cell Line ; Factor VIIa/metabolism ; Humans ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-1/metabolism ; Macrophages/metabolism ; Mice ; Protein Binding ; Receptors, LDL/metabolism ; Recombinant Proteins/metabolism ; Serpins/metabolism ; Thromboplastin/metabolism ; Time Factors ; Tumor Suppressor Proteins/metabolism | ||||||||||
| Chemical Substances | Antithrombins ; Carrier Proteins ; LRP1 protein, human ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-1 ; Lrp1 protein, mouse ; Receptors, LDL ; Recombinant Proteins ; Serpins ; Tumor Suppressor Proteins ; Thromboplastin (9035-58-9) ; Factor VIIa (EC 3.4.21.21) | ||||||||||
| Language | English | ||||||||||
| Publishing date | 2016-10-25 | ||||||||||
| Publishing country | England | ||||||||||
| Document type | Journal Article ; Research Support, Non-U.S. Gov't | ||||||||||
| ZDB-ID | 2112661-6 | ||||||||||
| ISSN | 1538-7836 ; 1538-7933 | ||||||||||
| ISSN (online) | 1538-7836 | ||||||||||
| ISSN | 1538-7933 | ||||||||||
| DOI | 10.1111/jth.13502 | ||||||||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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