RATIONALE: The structural and functional integrity of the endothelium is crucial 
in maintaining vascular homeostasis and preventing atherosclerosis. Patients 
with systemic lupus erythematosus (SLE) have an increased risk of developing 
endothelial dysfunction and premature cardiovascular disease. Neutrophil 
extracellular trap (NET) formation is increased in SLE and has been proposed to 
contribute to endothelial damage, but the mechanism remains unclear.
OBJECTIVE: To determine the mechanism by which enhanced NET formation by 
low-density granulocytes (LDGs) in SLE contributes to endothelial damage and 
disrupts the endothelium.
RESULTS: The putative role of NET-externalised matrix metalloproteinases (MMPs) 
in altering the functional integrity of the endothelium was examined. MMP-9 
externalised by lupus LDGs during NET formation specifically impaired murine 
aortic endothelium-dependent vasorelaxation and induced endothelial cell 
apoptosis. Endothelial dysfunction correlated with the activation of endothelial 
MMP-2 by MMP-9 present in NETs, while inhibition of MMP-2 activation restored 
endothelium-dependent function and decreased NET-induced vascular cytotoxicity. 
Moreover, immunogenic complexes composed of MMP-9 and anti-MMP-9 were identified 
in SLE sera. These complexes, as well as anti-MMP-9 autoantibodies, induced 
NETosis and enhanced MMP-9 activity.
CONCLUSIONS: These observations implicate activation of endothelial MMP-2 by 
MMP-9 contained in NETs as an important player in endothelial dysfunction, and 
MMP-9 as a novel self-antigen in SLE. These results further support that 
aberrant NET formation plays pathogenic roles in SLE.