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

• Published in: Life sciences (1973) Vol. 78; no. 9; pp. 1021 - 1028
• Main Authors: Abe, Naoki, Osanai, Tomohiro, Fujiwara, Takayuki, Kameda, Kunihiko, Matsunaga, Toshiro, Okumura, Ken
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 25-01-2006
• Subjects: Animals; Antioxidants - pharmacology; Basigin - biosynthesis; C-reactive protein; C-Reactive Protein - antagonists & inhibitors; C-Reactive Protein - pharmacology; Dinoprost - analogs & derivatives; Dinoprost - biosynthesis; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Extracellular matrix metalloproteinase inducer; 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; Matrix metalloproteinase-9; Rats; Reverse Transcriptase Polymerase Chain Reaction; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Up-Regulation - drug effects; Matrix metalloproteinase-9; C-reactive protein; Fluvastatin; Extracellular matrix metalloproteinase inducer
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2005.06.015

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.
Rat peritoneal macrophages were collected by peritoneal lavage, and were incubated in the presence or absence of CRP. CRP at 5 μg/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 μg/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 μg/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 μg/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
2α levels in the condition media.
CRP is an activator for macrophages to enhance EMMPRIN and MMP-9 expression. Fluvastatin inhibits them presumably through its antioxidant effect.