NDLI: Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13

Content Provider	PubMed Central
Author	Chen, Junmei Fu, Xiaoyun Wang, Yi Ling, Minhua Mcmullen, Brad Kulman, John Chung, Dominic W. López, José A.
Abstract	Elevated plasma von Willebrand factor (VWF) and low ADAMTS13 activity have been reported in several inflammatory states, including sepsis and acute respiratory distress syndrome. One hallmark of inflammation is neutrophil activation and production of reactive oxygen species, including superoxide radical, hydrogen peroxide, and hypochlorous acid (HOCl). HOCl is produced from hydrogen peroxide and chloride ions through the action of myeloperoxidase. HOCl can oxidize methionine to methionine sulfoxide and tyrosine to chlorotyrosine. This is of interest because the ADAMTS13 cleavage site in VWF, the Tyr1605-Met1606 peptide bond, contains both oxidation-prone residues. We hypothesized that HOCl would oxidize either or both of these residues and possibly inhibit ADAMTS13-mediated cleavage. We therefore treated ADAMTS13 substrates with HOCl and examined their oxidative modification by mass spectrometry. Met1606 was oxidized to the sulfoxide in a concentration-dependent manner, with complete oxidation at 75μM HOCl, whereas only a miniscule percentage of Tyr1605 was converted to chlorotyrosine. The oxidized substrates were cleaved much more slowly by ADAMTS13 than the nonoxidized substrates. A similar result was obtained with multimeric VWF. Taken together, these findings indicate that reactive oxygen species released by activated neutrophils have a prothrombotic effect, mediated in part by inhibition of VWF cleavage by ADAMTS13.
Related Links	http://dx.doi.org/10.1182/blood-2009-03-213967
Ending Page	712
Page Count	7
Starting Page	706
File Format	PDF
ISSN	00064971
e-ISSN	15280020
Journal	Blood
Issue Number	3
Volume Number	115
Language	English
Publisher	American Society of Hematology
Publisher Date	2010-01-21
Access Restriction	Open
Rights Holder	American Society of Hematology
Subject Keyword	Immunology Cell Biology Biochemistry Hematology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Hematology Biochemistry Immunology

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