(Circulation. 2001;103:993.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits
From the Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (Y.F., P.L., E.R., C.C.H., M.A.); and the Biosafety Research Center, Foods, Drugs, and Pesticides, Shizuoka (M.E., Y.H.), and the Institute of Experimental Animals, Kobe University School of Medicine, Kobe (M.S.), Japan.
Correspondence to Masanori Aikawa, MD, PhD, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail maikawa{at}rics.bwh.harvard.edu
Background—Acute coronary syndromes often result from rupture of vulnerable plaques. The collagen content of plaques probably regulates their stability. This study tested whether HMG-CoA reductase inhibitors (statins) alter interstitial collagen gene expression or matrix metalloproteinase (MMP) levels in rabbit atheroma.
Methods and Results—We administered equihypocholesterolemic doses of pravastatin (a hydrophilic statin, 50 mg · kg-1 · d-1, n=9), fluvastatin (a cell-permeant lipophilic statin, 20 mg · kg-1 · d-1, n=10), or placebo (n=10) to mature Watanabe heritable hyperlipidemic rabbits for 52 weeks. The fluvastatin group achieved a much higher peak plasma concentration (23.7 µmol/L) than did the pravastatin group (1.3 µmol/L) under these conditions. Immunohistochemistry revealed that MMP-1, MMP-3, and MMP-9 expression by macrophages in the intima was lower in both the pravastatin and fluvastatin groups than in the placebo group, whereas there was no difference in macrophage numbers. Numbers of intimal smooth muscle cells (SMCs) (identified by immunohistochemistry) and expression of type I procollagen mRNA (detected by in situ hybridization), however, were significantly higher in the pravastatin group than in the fluvastatin group. Treatment with pravastatin, but not fluvastatin, preserved interstitial collagen content in vivo (detected by picrosirius red polarization). In vitro, fluvastatin, but not pravastatin, decreased numbers of rabbit and human aortic SMCs without altering procollagen I mRNA expression.
Conclusions—This study showed that statins can reduce MMP expression in atheroma and that cell-permeant statins can decrease SMC number and collagen gene expression in vivo.
Key Words: collagen • muscle, smooth • atherosclerosis
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|
|
|
|
|
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|
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|
|
|
|
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|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 L. K. Newby, A. Kristinsson, M. V. Bhapkar, P. E. Aylward, A. P. Dimas, W. W. Klein, D. K. McGuire, D. J. Moliterno, F. W. A. Verheugt, W. D. Weaver, et al. Early Statin Initiation and Outcomes in Patients With Acute Coronary Syndromes JAMA, June 19, 2002; 287(23): 3087 - 3095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
 |
|
 W. Palinski and S. Tsimikas Immunomodulatory Effects of Statins: Mechanisms and Potential Impact on Arteriosclerosis J. Am. Soc. Nephrol., June 1, 2002; 13(6): 1673 - 1681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
I. Loftus and M. Thompson The role of matrix metalloproteinases in vascular disease Vascular Medicine, May 1, 2002; 7(2): 117 - 133. [Abstract] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
P. Libby, P. M. Ridker, and A. Maseri Inflammation and Atherosclerosis Circulation, March 5, 2002; 105(9): 1135 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
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|
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