Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques.
OBJECTIVE
Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine and has been shown to play a role in pathogenesis of atherosclerosis. The aim of this study is to investigate the potential role of MIF in the destabilization of atherosclerotic plaques by stimulation of vascular MMP-1 expression.


METHODS
MIF and matrix metalloproteinase protein-1 (MMP-1) expression in human atherosclerotic plaques were determined by immunohistochemistry. The functional activity of MIF was examined by its ability to induce MMP-1 expression in vascular smooth muscle cells (VSMCs) in vitro.


RESULTS
Two-color immunohistochemistry demonstrated that MIF was strongly upregulated in vulnerable, but not in fibrous plaques. Upregulation of vascular MIF was associated with macrophage accumulation (p<0.01), strong expression of vascular MMP-1 (p<0.001), and collagenolysis in vulnerable atheromatous plaques, but not in the fibrous lesions. Co-expression of MIF and MMP-1 in vulnerable atheromatous plaques appeared to contribute to the weakening of fibrous caps and plaque disruption. The role of MIF in vascular MMP-1 expression was demonstrated by the ability of MIF to directly stimulate VSMCs to express MMP-1 mRNA and protein, and to increase MMP-1 activity in a dose- and time-dependent manner, which was blocked by a neutralizing MIF antibody (p<0.001).


CONCLUSIONS
MIF and MMP-1 are markedly upregulated in vulnerable atheromatous plaques and are associated with the weakening of the fibrous cap. The ability of MIF to induce MMP-1 expression and collagenolytic activity in VSMCs suggests that MIF may play a role in the destabilization of human atherosclerotic plaques.
Kong
Yao-Zhong
YZ
The First People's Foshan Hospital, Foshan, Guangdong, China.
Huang
Xiao-Ru
XR
Ouyang
Xiaosen
X
Tan
Jei-Ju
JJ
Fingerle-Rowson
Gunter
G
Bacher
Michael
M
Mu
Wei
W
Scher
Larry A
LA
Leng
Lin
L
Bucala
Richard
R
Lan
Hui Y
HY
D001161:Arteriosclerosis / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008263:Macrophage Migration-Inhibitory Factors / Q000494:pharmacology / Q000502:physiology*; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D008263:Macrophage Migration-Inhibitory Factors; D020781:Matrix Metalloproteinase 1