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


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.
Abe
Naoki
N
Second Department of Internal Medicine, Hirosaki University School of Medicine 5 Zaifu, Hirosaki, Aomori, Japan.
Osanai
Tomohiro
T
Fujiwara
Takayuki
T
Kameda
Kunihiko
K
Matsunaga
Toshiro
T
Okumura
Ken
K
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D051926:Basigin / Q000096:biosynthesis*; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D019715:Tissue Inhibitor of Metalloproteinase-1; D051926:Basigin; C075750:8-epi-prostaglandin F2alpha; D000077340:Fluvastatin; D002097:C-Reactive Protein; D015237:Dinoprost; D020780:Matrix Metalloproteinase 9