C-reactive protein-induced upregulation of extracellular matrix metalloproteinase inducer in macrophages: inhibitory effect of fluvastatin

Life Sci. 2006 Jan 25;78(9):1021-8. doi: 10.1016/j.lfs.2005.06.015. Epub 2005 Sep 22.


Objective: Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase (MMP)-9 were reported to be expressed at the macrophage-rich area in human coronary atherosclerotic plaque. We examined whether C-reactive protein (CRP) activates macrophages to express EMMPRIN and MMP-9 in vitro and whether statins inhibit it.

Methods and results: Rat peritoneal macrophages were collected by peritoneal lavage, and were incubated in the presence or absence of CRP. CRP at 5 microg/ml increased the gene expression of EMMPRIN relative to GAPDH, measured by RT-PCR, by 1.67+/-0.07 fold at 24 h and by 1.85+/-0.49 fold at 48 h (both p<0.05). The gene expression of MMP-9 in the presence of CRP at 5 microg/ml was followed by 1.36+/-0.11 fold increase at 24 h and by 3.95+/-0.81 fold at 48 h (both p<0.05). CRP at 5 microg/ml for 48 h increased by 6 fold MMP-9 activity, measured by zymography, without affecting tissue inhibitor of metalloproteinases-1. Boiled CRP at 5 mug/ml for 48 h unaffected MMP-9 activity. Fluvastatin blocked the CRP-induced increases in EMMPRIN and MMP-9 expression and activity. Diphenylene iodonium, an inhibitor of NADPH oxidase, had a similar effect on MMP-9 activity. Fluvastatin suppressed the CRP-induced increases in 8-epi-prostaglandin F(2alpha) levels in the condition media.

Conclusions: CRP is an activator for macrophages to enhance EMMPRIN and MMP-9 expression. Fluvastatin inhibits them presumably through its antioxidant effect.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Basigin / biosynthesis*
  • C-Reactive Protein / antagonists & inhibitors*
  • C-Reactive Protein / pharmacology*
  • Dinoprost / analogs & derivatives
  • Dinoprost / biosynthesis
  • Dose-Response Relationship, Drug
  • Electrophoresis, Polyacrylamide Gel
  • Fatty Acids, Monounsaturated / pharmacology*
  • Fluvastatin
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • In Vitro Techniques
  • Indoles / pharmacology*
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Matrix Metalloproteinase 9 / biosynthesis
  • Matrix Metalloproteinase 9 / genetics
  • Rats
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Inhibitor of Metalloproteinase-1 / biosynthesis
  • Up-Regulation / drug effects


  • Antioxidants
  • Fatty Acids, Monounsaturated
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Tissue Inhibitor of Metalloproteinase-1
  • Basigin
  • 8-epi-prostaglandin F2alpha
  • Fluvastatin
  • C-Reactive Protein
  • Dinoprost
  • Matrix Metalloproteinase 9