title: Evidence for vascular macrophage migration inhibitory factor in destabilization of human atherosclerotic plaques.
abstract: 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.
authors.affiliation: The First People's Foshan Hospital, Foshan, Guangdong, China.
authors.forename: Yao-Zhong
authors.initials: YZ
authors.lastname: Kong
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Huang
authors.forename: Xiaosen
authors.initials: X
authors.lastname: Ouyang
authors.forename: Jei-Ju
authors.initials: JJ
authors.lastname: Tan
authors.forename: Gunter
authors.initials: G
authors.lastname: Fingerle-Rowson
authors.forename: Michael
authors.initials: M
authors.lastname: Bacher
authors.forename: Wei
authors.initials: W
authors.lastname: Mu
authors.forename: Larry A
authors.initials: LA
authors.lastname: Scher
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Hui Y
authors.initials: HY
authors.lastname: Lan
mesh_terms: 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
chemical_list: D008263:Macrophage Migration-Inhibitory Factors; D020781:Matrix Metalloproteinase 1