Oxidized von Willebrand factor is efficiently cleaved by serine proteases from primary granules of leukocytes: divergence from adamts-13

Raimondo De Cristofaro, Stefano Lancellotti, Sergio Rutella

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

13 Citazioni (Scopus)

Abstract

Background: The leukocyte serine proteases (LSPs) elastase, proteinase 3 and cathepsin G cleave von Willebrand factor (VWF) near or at the same cleavage site (Tyr1605-Met1606) as ADAMTS-13, the metalloprotease that specifically controls the proteolytic processing of VWF. Recent studies showed that oxidation of VWF at Met1606 with formation of sulfoxy-Met (MetSO) severely impairs its proteolysis by ADAMTS-13. Design and Methods: This study was aimed at assessing whether or not oxidation of VWF by reactive oxygen species (ROS) may also affect its cleavage by elastase, proteinase 3 and cathepsin G. In this study the catalytic specificity of hydrolysis by LSPs of the VWF peptide substrate VWF74 and full length VWF, both in unaltered or oxidized form was measured by RP-HPLC, electrophoretic and mass spectrometry methods. Results: LSPs cleave both VWF multimers and VWF74 near or at the same peptide bond hydrolyzed by ADAMTS-13 with k(cat) /K(m) values similar to that of the metalloprotease. However, at variance with ADAMTS-13, cathepsin G cleaved VWF74 containing a MetSO residue at position 1606 with a k(cat) /K(m) value higher than VWF74, whereas the catalytic efficiency of both elastase and proteinase 3 was unaffected by the substitution of Met1606 with MetSO. Likewise, oxidation of VWF multimers by HClO and ROS, produced by activated leukocytes, improved their hydrolysis by LSPs. Conclusions: Oxidation by leukocyte ROS has a net positive effect on cleavage of VWF multimers by LSPs, under conditions where high concentrations of oxidant species would severely reduce the proteolytic efficiency of ADAMTS-13.
Lingua originaleEnglish
pagine (da-a)1620-1627
Numero di pagine8
RivistaJournal of Thrombosis and Haemostasis
Volume2011
Stato di pubblicazionePubblicato - 2011

Keywords

  • Leukocyte serine proteases
  • Oxidative stress
  • VWF

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