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Macrophage migration inhibitory factor induces MMP-9 expression: implications for destabilization of human
Yao-Zhong Kong1, Xiyong Yu, Jia-Ju Tang
1Department of Medicine, The First People's Foshan Hospital, Foshan, Guangdong, China.
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.
Insights
Macrophage migration inhibitory factor (MIF) promotes atherosclerotic plaque destabilization by increasing matrix metalloproteinase-9 (MMP-9) expression. This study links MIF and MMP-9 to vulnerable plaques and weakened fibrous caps in humans.
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Medicine
Background:
- Macrophage migration inhibitory factor (MIF) is implicated in atherogenesis.
- Matrix metalloproteinase-9 (MMP-9) expression is linked to atherosclerotic plaque instability.
Purpose of the Study:
- To investigate the hypothesis that MIF contributes to atherosclerotic plaque destabilization by stimulating MMP-9 expression.
- To examine the expression of MIF and MMP-9 in human atherosclerotic plaques.
- To determine the role of MIF in inducing MMP-9 expression in vitro.
Main Methods:
- Two-color immunohistochemistry was used to analyze MIF and MMP-9 expression in human atherosclerotic plaques.
- In vitro studies assessed MIF's effect on MMP-9 expression in vascular smooth muscle cells (VSMCs) and macrophages.
- Neutralizing MIF antibodies were used to block MIF-induced MMP-9 expression.
Main Results:
- MIF and MMP-9 were significantly upregulated in vulnerable atheromatous plaques compared to fibrous lesions.
- Upregulation of MIF and MMP-9 correlated with weakened fibrous caps in vulnerable plaques.
- MIF directly induced MMP-9 mRNA and protein expression in VSMCs and macrophages in a dose- and time-dependent manner.
Conclusions:
- MIF and MMP-9 are markedly upregulated in vulnerable human atherosclerotic plaques.
- MIF's ability to induce MMP-9 expression suggests a key role in atherosclerotic plaque destabilization.
- Targeting the MIF-MMP-9 pathway may offer therapeutic strategies for vulnerable atherosclerotic plaques.
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