Macrophage migration inhibitory factor induces MMP-9 expression: implications for destabilization of human atherosclerotic plaques.
Macrophage migration inhibitory factor (MIF) has been shown to participate in both experimental and human atherogenesis. Expression of MMP-9 has been shown to play a role in the instability of atherosclerotic plaque. Thus, we hypothesize that MIF may participate in the destabilization of atherosclerotic plaques by stimulating MMP-9 expression. This hypothesis was investigated by examining the expression of MIF and MMP-9 in human atherosclerotic plaques using two-color immunostaining and by determining the potential role of MIF in the induction of MMP-9 expression in vascular smooth muscle cells (VSMC) and macrophages in vitro. Two-color immunohistochemistry demonstrated that MIF was strongly upregulated by macrophages and VSMCs. This was associated with marked increase in MMP-9 expression in vulnerable atheromatous plaques, but not in the fibrous lesions. Upregulation of MIF and MMP-9 in vulnerable atheromatous plaques was associated with the weakening of fibrous caps. The role of MIF in MMP-9 expression was demonstrated by the ability of MIF to directly induce MMP-9 mRNA and protein expression in macrophages and in VSMCs in a dose and time-dependent manner, which was blocked by a neutralizing MIF antibody. In conclusion, MIF and MMP-9 are markedly upregulated in vulnerable atheromatous plaques. The ability of MIF to induce MMP-9 expression in VSMCs and macrophages suggests that MIF may play a role in the destabilization of human atherosclerotic plaques.
Kong
Yao-Zhong
YZ
Department of Medicine, The First People's Foshan Hospital, Foshan, Guangdong, China.
Yu
Xiyong
X
Tang
Jia-Ju
JJ
Ouyang
Xiaosen
X
Huang
Xiao-Ru
XR
Fingerle-Rowson
Gunter
G
Bacher
Michael
M
Scher
Larry A
LA
Bucala
Richard
R
Lan
Hui Y
HY
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D006801:Humans; D008263:Macrophage Migration-Inhibitory Factors / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D015854:Up-Regulation
D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D020780:Matrix Metalloproteinase 9