(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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K. K. Koh, J. W. Son, J. Y. Ahn, D. K. Jin, H. S. Kim, Y. M. Choi, D. S. Kim, E.-M. Jeong, G. S. Park, I. S. Choi, et al. Comparative Effects of Diet and Statin on NO Bioactivity and Matrix Metalloproteinases in Hypercholesterolemic Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): e19 - 23. [Abstract] [Full Text] [PDF]
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G. K. Sukhova, J. K. Williams, and P. Libby Statins Reduce Inflammation in Atheroma of Nonhuman Primates Independent of Effects on Serum Cholesterol Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): 1452 - 1458. [Abstract] [Full Text] [PDF]
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P. Schoenhagen, E. M. Tuzcu, and S. G. Ellis Plaque Vulnerability, Plaque Rupture, and Acute Coronary Syndromes: (Multi)-Focal Manifestation of a Systemic Disease Process Circulation, August 13, 2002; 106(7): 760 - 762. [Full Text] [PDF]
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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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 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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R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]
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P. Libby and M. Aikawa Vitamin C, Collagen, and Cracks in the Plaque Circulation, March 26, 2002; 105(12): 1396 - 1398. [Full Text] [PDF]
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K. E. Ferrier, M. H. Muhlmann, J.-P. Baguet, J. D. Cameron, G. L. Jennings, A. M. Dart, and B. A. Kingwell Intensive cholesterol reduction lowers blood pressure and large artery stiffness in isolated systolic hypertension J. Am. Coll. Cardiol., March 20, 2002; 39(6): 1020 - 1025. [Abstract] [Full Text] [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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S. H. Wilson, J. Herrmann, L. O. Lerman, D. R. Holmes Jr, C. Napoli, E. L. Ritman, and A. Lerman Simvastatin Preserves the Structure of Coronary Adventitial Vasa Vasorum in Experimental Hypercholesterolemia Independent of Lipid Lowering Circulation, January 29, 2002; 105(4): 415 - 418. [Abstract] [Full Text] [PDF]
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H. V. Anderson, J. McNatt, F. J. Clubb, M. Herman, J.-P. Maffrand, F. DeClerck, C. Ahn, L. M. Buja, and J. T. Willerson Platelet Inhibition Reduces Cyclic Flow Variations and Neointimal Proliferation in Normal and Hypercholesterolemic-Atherosclerotic Canine Coronary Arteries Circulation, November 6, 2001; 104(19): 2331 - 2337. [Abstract] [Full Text] [PDF]
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M. Takemoto and J. K. Liao Pleiotropic Effects of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Arterioscler Thromb Vasc Biol, November 1, 2001; 21(11): 1712 - 1719. [Abstract] [Full Text] [PDF]
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 A. Farzaneh-Far, J. Rudd, and P. L Weissberg Inflammatory mechanisms: Ischaemic heart disease Br. Med. Bull., October 1, 2001; 59(1): 55 - 68. [Abstract] [Full Text] [PDF]
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P. Libby Current Concepts of the Pathogenesis of the Acute Coronary Syndromes Circulation, July 17, 2001; 104(3): 365 - 372. [Full Text] [PDF]
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M. A. Albert, E. Danielson, N. Rifai, P. M Ridker, and for the PRINCE Investigators Effect of Statin Therapy on C-Reactive Protein Levels: The Pravastatin Inflammation/CRP Evaluation (PRINCE): A Randomized Trial and Cohort Study JAMA, July 4, 2001; 286(1): 64 - 70. [Abstract] [Full Text] [PDF]
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M. Aikawa and P. Libby Vascular inflammation and activation: new targets for lipid lowering Eur. Heart J. Suppl., May 1, 2001; 3(suppl_B): B3 - B11. [Abstract] [PDF]
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P. M. Ridker, N. Rifai, and S. P. Lowenthal Rapid Reduction in C-Reactive Protein With Cerivastatin Among 785 Patients With Primary Hypercholesterolemia Circulation, March 6, 2001; 103(9): 1191 - 1193. [Abstract] [Full Text] [PDF]
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Y. Fukumoto, P. Libby, E. Rabkin, C. C. Hill, M. Enomoto, Y. Hirouchi, M. Shiomi, and M. Aikawa Statins Alter Smooth Muscle Cell Accumulation and Collagen Content in Established Atheroma of Watanabe Heritable Hyperlipidemic Rabbits Circulation, February 20, 2001; 103(7): 993 - 999. [Abstract] [Full Text] [PDF]
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R. Baetta, M. Camera, C. Comparato, C. Altana, M. D. Ezekowitz, and E. Tremoli Fluvastatin Reduces Tissue Factor Expression and Macrophage Accumulation in Carotid Lesions of Cholesterol-Fed Rabbits in the Absence of Lipid Lowering Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 692 - 698. [Abstract] [Full Text] [PDF]
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M. Eto, T. Kozai, F. Cosentino, H. Joch, and T. F. Luscher Statin Prevents Tissue Factor Expression in Human Endothelial Cells: Role of Rho/Rho-Kinase and Akt Pathways Circulation, April 16, 2002; 105(15): 1756 - 1759. [Abstract] [Full Text] [PDF]
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