(Circulation. 2001;103:276.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
An HMG-CoA Reductase Inhibitor, Cerivastatin, Suppresses Growth of Macrophages Expressing Matrix Metalloproteinases and Tissue Factor In Vivo and In Vitro
From the Cardiovascular Division, Department of Medicine (M.A., S.S., S.J.V., Y. Fukumoto, Y. Furukawa, P.L.) and Department of Pathology (E.R., F.J.S.), Brigham and Women’s Hospital and Harvard Medical School, Boston, Mass, and Institute for Experimental Animals, Kobe University School of Medicine (M.S.), Kobe, Japan.
Correspondence to Masanori Aikawa, MD, PhD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 309, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu
Background—Unstable atherosclerotic plaques that cause acute coronary events usually contain abundant macrophages expressing matrix metalloproteinases (MMPs) and tissue factor (TF), molecules that probably contribute to plaque rupture and subsequent thrombus formation. Lipid lowering with HMG-CoA reductase inhibitors reduces acute coronary events.
Methods and Results—To
test whether lipid lowering with an HMG-CoA reductase inhibitor retards
macrophage accumulation in rabbit atheroma, we administered
cerivastatin to immature Watanabe heritable hyperlipidemic rabbits
(cerivastatin 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 accumulation 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
cerivastatin treatment. Cerivastatin reduced the number of macrophages
expressing 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 (
0.01
µmol/L) also reduced growth, proteolytic activity due to MMP-9, and
TF expression in cultured human
monocyte/macrophages.
Conclusions—These results suggest that lipid lowering with HMG-CoA reductase inhibitors alters plaque biology by reducing proliferation and activation of macrophages, prominent sources of molecules responsible for plaque instability and thrombogenicity.
Key Words: atherosclerosis • inflammation • thrombosis • hypercholesterolemia • metalloproteinases
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