Abstract:
:Carbamylation is a non-enzymatic post-translational modification induced upon exposure of free amino groups to urea-derived cyanate leading to irreversible changes of protein charge, structure and function. Levels of carbamylated proteins increase significantly in chronic kidney disease and carbamylated albumin is considered as an important biomarker indicating mortality risk. High plasma concentrations and long half-life make fibrinogen a prime target for carbamylation. As aggregation and cross-linking of fibrin monomers rely on lysine residues, it is likely that carbamylation impacts fibrinogen processing. In this study we investigated carbamylation levels of fibrinogen from kidney disease patients as well as the impact of carbamylation on fibrinogen cleavage by thrombin, fibrin polymerisation and cross-linking in vitro. In conjunction, all these factors determine clot structure and stability and thus control biochemical and mechanical properties. LC-MS/MS analyses revealed significantly higher homocitrulline levels in patient fibrinogen than in fibrinogen isolated from control plasma. In our in vitro studies we found that although carbamylation does not affect thrombin cleavage per se, it alters fibrin polymerisation kinetics and impairs cross-linking and clot degradation. In addition, carbamylated fibrin clots had reduced fiber size and porosity associated with decreased mechanical stability. Using mass spectroscopy, we discovered that N-terminally carbamylated fibrinopeptide A was generated in this process and acted as a strong neutrophil chemoattractant potentially mediating recruitment of inflammatory cells to sites of fibrin(ogen) turnover. Taken together, carbamylation of fibrinogen seems to play a role in aberrant fibrin clot formation and might be involved in haemostatic disorders associated with chronic inflammatory diseases.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Binder V,Bergum B,Jaisson S,Gillery P,Scavenius C,Spriet E,Nyhaug AK,Roberts HM,Chapple ILC,Hellvard A,Delaleu N,Mydel Pdoi
10.1160/TH16-09-0704subject
Has Abstractpub_date
2017-05-03 00:00:00pages
899-910issue
5eissn
0340-6245issn
2567-689Xpii
16-09-0704journal_volume
117pub_type
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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pub_type: 杂志文章
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journal_title:Thrombosis and haemostasis
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