Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13
Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13
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DOI：
10.1182/blood-2009-03-213967
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发表时间：
2010-01-21
期刊：
影响因子：
20.3
通讯作者：
Lopez, Jose A.
中科院分区：
文献类型：
--
作者：
Chen, Junmei;Fu, Xiaoyun;Lopez, Jose A.
血浆血管性血友病因子（VWF）升高和ADAMTS13活性低已被报道在几种炎症状态下，包括败血症和急性呼吸窘迫综合征。炎症的一个标志是中性粒细胞的活化和活性氧的产生，包括超氧自由基、过氧化氢和次氯酸（HOCl）。HOCl是由过氧化氢和氯离子通过髓过氧化物酶的作用产生的。HOCl能将蛋氨酸氧化为蛋氨酸亚砜，将酪氨酸氧化为氯酪氨酸。这是一个有趣的发现，因为VWF中的ADAMTS13切割位点，Tyr(1605)-Met（1606）肽键，包含两个容易氧化的残基。我们假设HOCl会氧化这些残基中的一个或两个，并可能抑制adamts13介导的裂解。因此，我们用HOCl处理了DAMTS13底物，并用质谱法检测了它们的氧化修饰。Met（1606）以浓度依赖的方式被氧化为亚砜，在75 μ M HOCl下完全氧化，而Tyr（1605）只有极少量被转化为氯酪氨酸。氧化底物被ADAMTS13切割的速度比未氧化底物慢得多。用多聚VWF得到了类似的结果。综上所述，这些发现表明，活化的中性粒细胞释放的活性氧具有促血栓作用，部分是通过ADAMTS13抑制VWF切割介导的。（血液。2010;115:706-712）
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 Tyr(1605)-Met(1606) 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 DAMTS13 substrates with HOCl and examined their oxidative modification by mass spectrometry. Met(1606) was oxidized to the sulfoxide in a concentration-dependent manner, with complete oxidation at 75 mu M HOCl, whereas only a miniscule percentage of Tyr(1605) 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. (Blood. 2010; 115: 706-712)