An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro

Background-Unstable atherosclerotic plaques that cause acute coronary event s usually contain abundant macrophages expressing matrix metalloproteinases (MMPs) and tissue factor (TF), molecules that probably contribute to plaqu e rupture and subsequent thrombus formation. Lipid lowering with HMG-CoA re ductase inhibitors reduces acute coronary events. Methods and Results-To test whether lipid lowering with an HMC-CoA reductas e inhibitor retards macrophage accumulation in rabbit atheroma, we administ ered cerivastatin to immature Watanabe heritable hyperlipidemic rabbits (ce rivastatin group, n=10, cerivastatin 0.6 mg . kg(-1).d(-1); control group, n=9, saline 0.6 mL . kg(-1).d(-1)) for 32 weeks and measured macrophage acc umulation and expression of MMPs and TF. Serum cholesterol levels after 32 weeks were 809+/-40 mg/dL (control group) and 481+/-24 mg/dL (treated group ). Cerivastatin diminished accumulation of macrophages in aortic atheroma. Macrophage expression of MMP-1, MMP-3, MMP-9, and TF also decreased with ce rivastatin treatment. Cerivastatin reduced the number of macrophages expres sing histone mRNA (a sensitive marker of cell proliferation) detected by in situ hybridization but did not alter macrophages bearing a marker of death (TUNEL staining). Cerivastatin treatment (greater than or equal to0.01 mu mol/L) also reduced growth, proteolytic activity due to MMP-9, and TF expre ssion in cultured human monocyte/macrophages. Conclusions-There results suggest that lipid lowering with HMG-CoA reductas e inhibitors alters plaque biology by reducing proliferation and activation of macrophages, prominent sources of molecules responsible for plaque inst ability and thrombogenicity.