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

Objective: Extracellular matrix metalloproteinase inducer (ENIMPRIN) and matrix metalloprotinase (MM-P)-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 mu g/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 mu g/ml was followed by 1.36 +/- 0.11 fold increase at 24 It and by 3.95 +/- 0.81 fold at 48 h (both p < 0.05). CRP at 5 mu g/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 mu g/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-2 alpha 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. (c) 2005 Elsevier Inc. All rights reserved.