Myeloperoxidase interacts with endothelial cell-surface cytokeratin 1 and modulates bradykinin production by the plasma kallikrein-kinin system

被引:45
作者
Astern, Joshua M.
Pendergraft, William F., III
Falk, Ronald J.
Jennette, J. Charles
Schmaier, Alvin H.
Mahdi, Fakhri
Preston, Gloria A.
机构
[1] Univ N Carolina, Kidney Ctr, Chapel Hill, NC 27599 USA
[2] Univ N Carolina, Div Nephrol & Hypertens, Chapel Hill, NC 27599 USA
[3] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA
[4] Case Western Reserve Univ, Cleveland, OH 44106 USA
[5] Univ Michigan, Ann Arbor, MI 48109 USA
关键词
D O I
10.2353/ajpath.2007.060831
中图分类号
R36 [病理学];
学科分类号
100104 ;
摘要
During an inflammatory state, functional myeloperoxidase (MPO) is released into the vessel as a result of intravascular neutrophil degradation. One mechanism of resulting cellular injury involves endothelial internalization of MPO, which causes oxidative damage and impairs endothelial signaling. We report the discovery of a protein that facilitates MPO internalization, cytokeratin 1 (CK1), identified using affinity chromatography and mass spectrometry. CK1 interacts with MPO in vitro, even in the presence of 100% human plasma, thus substantiating biological relevance. immunofluorescent microscopy confirmed that MPO added to endothelial cells can co-localize with endogenously expressed CK1. CK1 acts as a scaffolding protein for the assembly of the vasoregulatory plasma kallikrein-kinin system; thus we explored whether MPO and high molecular weight kininogen (HK) reside on CK1 together or whether they compete for binding. The data support cooperative binding of MPO and HK on cells such that MPO masked the plasma kallikrein cleavage site on HK, and MPO-generated oxidants caused inactivation of both HK and kallikrein. Collectively, interactions between MPO and the components of the plasma kallikreinkinin system resulted in decreased bradykinin production. This study identifies CK1 as a facilitator of MPO-mediated vascular responses and thus provides a new paradigm by which MPO affects vasoregulatory systems.
引用
收藏
页码:349 / 360
页数:12
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