title: Macrophage migration inhibitory factor induces MMP-9 expression: implications for destabilization of human atherosclerotic plaques.
abstract: 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.
authors.affiliation: Department of Medicine, The First People's Foshan Hospital, Foshan, Guangdong, China.
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Kong
authors.forename: Xiyong
authors.initials: X
authors.lastname: Yu
authors.forename: Jia-Ju
authors.initials: JJ
authors.lastname: Tang
authors.forename: Xiaosen
authors.initials: X
authors.lastname: Ouyang
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Gunter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Michael
authors.initials: M
authors.lastname: Bacher
authors.forename: Larry A
authors.initials: LA
authors.lastname: Scher
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: 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
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D011994:Recombinant Proteins; D020780:Matrix Metalloproteinase 9