Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques

Yao Zhong Kong, Xiao Ru Huang, Xiaosen Ouyang, Jei Ju Tan, Gunter Fingerle-Rowson, Michael Bacher, Wei Mu, Larry A. Scher, Lin Leng, Richard Bucala, Hui Y. Lan

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51 Scopus citations

Abstract

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. 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. 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). 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.

Original languageEnglish (US)
Pages (from-to)272-282
Number of pages11
JournalCardiovascular research
Volume65
Issue number1
DOIs
Publication statusPublished - Jan 1 2005
Externally publishedYes

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Keywords

  • Atherosclerosis
  • Cytokines (MIF)
  • Macrophages
  • Matrix metalloproteinases
  • Smooth muscle cells

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Kong, Y. Z., Huang, X. R., Ouyang, X., Tan, J. J., Fingerle-Rowson, G., Bacher, M., ... Lan, H. Y. (2005). Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques. Cardiovascular research, 65(1), 272-282. https://doi.org/10.1016/j.cardiores.2004.09.020