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From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular
Division, Department of Medicine, Brigham and Women's Hospital, Harvard
Medical School (M.A., E.R., Y.O., S.J.V., G.K.S., P.L.), and the Department of
Medicine, Dana-Farber Cancer Institute, Harvard Medical School (S.K.C.),
Boston, Mass; and the Department of Medicine, Dartmouth Medical School
(C.E.B.), Hanover, NH.
Correspondence to Dr Peter Libby, Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, LMRC 307, Boston, MA 02115. E-mail plibby{at}rics.bwh.harvard.edu
Background—Proteolytic enzyme
activity in lipid-rich atheroma may promote plaque rupture
and precipitate acute coronary syndromes. This study tested the
hypothesis that lipid lowering stabilizes plaques by reducing
proteolytic activity.
Methods and Results—We produced experimental atheroma
in 33 rabbits by balloon injury and an atherogenic diet (0.3%
cholesterol and 4.7% coconut oil) for 4 months. At that
time, 15 rabbits were killed (baseline group). The remaining animals
were divided into two groups: a hyperlipemic group continued to consume
a cholesterol-enriched diet (0.05% to 0.2%) for 16 more
months (n=5) and a lipid-lowering group consumed a purified chow diet
with no added cholesterol or fat for 8 (n=3) or 16 months
(n=10). Macrophage accumulation and interstitial
collagenase (matrix metalloproteinase-1, MMP-1) expression
in the lesion were measured by quantitative image analysis of
standardized sections of immunostained aortas. Baseline
lesions expressed high levels of MMP-1 and contained many
macrophages. These features of plaque instability persisted in
the hyperlipemic group. However, the lipid-lowering group showed
progressive reduction in both macrophage content and MMP-1
immunoreactivity with time. Aortic rings of the baseline and
hyperlipemic groups elaborated gelatinolytic,
caseinolytic, and elastinolytic activity attributable to MMP-2, MMP-3,
or MMP-9, monitored by SDS-PAGE zymography. Proteolytic activity
decreased markedly in the lipid-lowering group. Aortic content of
interstitial collagen, determined by sirius red staining,
increased in the lipid-lowering group compared with the baseline or
continued hyperlipemic groups, indicating that lipid lowering
reinforced the fibrous skeleton of the atheroma.
Conclusions—These results establish a mechanism by which lipid
lowering may stabilize vulnerable plaques by reduced expression and
activity of enzymes that degrade the arterial extracellular
matrix and render atheroma less susceptible to disruption
and thrombosis by favoring collagen accumulation in the fibrous cap.
© 1998 American Heart Association, Inc.
Basic Science Reports
Lipid Lowering by Diet Reduces Matrix Metalloproteinase Activity and Increases Collagen Content of Rabbit Atheroma
A Potential Mechanism of Lesion Stabilization
Key Words: metalloproteinases • atherosclerosis • diet • hypercholesterolemia • collagen
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U. Schonbeck, N. Gerdes, N. Varo, R. S. Reynolds, D. B. Horton, U. Bavendiek, L. Robbie, P. Ganz, S. Kinlay, and P. Libby Oxidized Low-Density Lipoprotein Augments and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors Limit CD40 and CD40L Expression in Human Vascular Cells Circulation, December 3, 2002; 106(23): 2888 - 2893. [Abstract] [Full Text] [PDF]
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L. G. Bucciarelli, T. Wendt, W. Qu, Y. Lu, E. Lalla, L. L. Rong, M. T. Goova, B. Moser, T. Kislinger, D. C. Lee, et al. RAGE Blockade Stabilizes Established Atherosclerosis in Diabetic Apolipoprotein E-Null Mice Circulation, November 26, 2002; 106(22): 2827 - 2835. [Abstract] [Full Text] [PDF]
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 J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [Abstract] [Full Text] [PDF]
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 K. Takayama, G. Garcia-Cardena, G. K. Sukhova, J. Comander, M. A. Gimbrone Jr., and P. Libby Prostaglandin E2 Suppresses Chemokine Production in Human Macrophages through the EP4 Receptor J. Biol. Chem., November 8, 2002; 277(46): 44147 - 44154. [Abstract] [Full Text] [PDF]
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 C. Kluft, R. Kleemann, and M.P.M. de Maat How best to counteract the enemies? By controlling inflammation in the coronary circulation Eur. Heart J. Suppl., November 1, 2002; 4(suppl_G): G53 - G65. [Abstract] [PDF]
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Z. S. Galis, C. Johnson, D. Godin, R. Magid, J. M. Shipley, R. M. Senior, and E. Ivan Targeted Disruption of the Matrix Metalloproteinase-9 Gene Impairs Smooth Muscle Cell Migration and Geometrical Arterial Remodeling Circ. Res., November 1, 2002; 91(9): 852 - 859. [Abstract] [Full Text] [PDF]
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A. C. Sposito and M. J. Chapman Statin Therapy in Acute Coronary Syndromes: Mechanistic Insight Into Clinical Benefit Arterioscler Thromb Vasc Biol, October 1, 2002; 22(10): 1524 - 1534. [Abstract] [Full Text] [PDF]
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P. Verhamme, R. Quarck, H. Hao, M. Knaapen, S. Dymarkowski, H. Bernar, J. Van Cleemput, S. Janssens, J. Vermylen, G. Gabbiani, et al. Dietary cholesterol withdrawal reduces vascular inflammation and induces coronary plaque stabilization in miniature pigs Cardiovasc Res, October 1, 2002; 56(1): 135 - 144. [Abstract] [Full Text] [PDF]
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M. Aikawa, S. Sugiyama, C. C. Hill, S. J. Voglic, E. Rabkin, Y. Fukumoto, F. J. Schoen, J. L. Witztum, and P. Libby Lipid Lowering Reduces Oxidative Stress and Endothelial Cell Activation in Rabbit Atheroma Circulation, September 10, 2002; 106(11): 1390 - 1396. [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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R. P. Choudhury, V. Fuster, J. J. Badimon, E. A. Fisher, and Z. A. Fayad MRI and Characterization of Atherosclerotic Plaque: Emerging Applications and Molecular Imaging Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1065 - 1074. [Abstract] [Full Text] [PDF]
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J. Hulthe and B. Fagerberg Circulating Oxidized LDL Is Associated With Subclinical Atherosclerosis Development and Inflammatory Cytokines (AIR Study) Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1162 - 1167. [Abstract] [Full Text] [PDF]
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T. C. Major, L. Liang, X. Lu, W. Rosebury, and T. M.A. Bocan Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Is Induced Upon Monocyte Differentiation and Is Expressed in Human Atheroma Arterioscler Thromb Vasc Biol, July 1, 2002; 22(7): 1200 - 1207. [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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M. R. Bennett Breaking the Plaque: Evidence for Plaque Rupture in Animal Models of Atherosclerosis Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 713 - 714. [Full Text] [PDF]
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M. D. Rekhter How to evaluate plaque vulnerability in animal models of atherosclerosis? Cardiovasc Res, April 1, 2002; 54(1): 36 - 41. [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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Z. S. Galis and J. J. Khatri Matrix Metalloproteinases in Vascular Remodeling and Atherogenesis: The Good, the Bad, and the Ugly Circ. Res., February 22, 2002; 90(3): 251 - 262. [Abstract] [Full Text] [PDF]
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 K.S. MOULTON Plaque Angiogenesis: Its Functions and Regulation Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 471 - 482. [Abstract] [PDF]
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G. S. Cherr, S. J. Motew, J. A. Travis, J. Fingerle, L. Fisher, M. Brandl, J. K. Williams, and R. L. Geary Metalloproteinase Inhibition and the Response to Angioplasty and Stenting in Atherosclerotic Primates Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 161 - 166. [Abstract] [Full Text] [PDF]
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E. Rabkin, M. Aikawa, J. R. Stone, Y. Fukumoto, P. Libby, and F. J. Schoen Activated Interstitial Myofibroblasts Express Catabolic Enzymes and Mediate Matrix Remodeling in Myxomatous Heart Valves Circulation, November 20, 2001; 104(21): 2525 - 2532. [Abstract] [Full Text] [PDF]
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G. J. Blake and P. M. Ridker Novel Clinical Markers of Vascular Wall Inflammation Circ. Res., October 26, 2001; 89(9): 763 - 771. [Abstract] [Full Text] [PDF]
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G. Sangiorgi, R. D'Averio, A. Mauriello, M. Bondio, M. Pontillo, S. Castelvecchio, S. Trimarchi, V. Tolva, G. Nano, V. Rampoldi, et al. Plasma Levels of Metalloproteinases-3 and -9 as Markers of Successful Abdominal Aortic Aneurysm Exclusion After Endovascular Graft Treatment Circulation, September 18, 2001; 104 (2009): I-288 - I-295. [Abstract] [Full Text] [PDF]
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P. Schoenhagen, K. M. Ziada, D. G. Vince, S. E. Nissen, and E. M. Tuzcu Arterial remodeling and coronary artery disease: the concept of "dilated" versus "obstructive" coronary atherosclerosis J. Am. Coll. Cardiol., August 1, 2001; 38(2): 297 - 306. [Abstract] [Full Text] [PDF]
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B. R. Kwak and F. Mach Statins Inhibit Leukocyte Recruitment: New Evidence for Their Anti-Inflammatory Properties Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1256 - 1258. [Full Text] [PDF]
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J.F. Bentzon and E. Falk Coronary plaques calling for action -- why, where and how many? Eur. Heart J. Suppl., August 1, 2001; 3(suppl_I): I3 - I9. [Abstract] [PDF]
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M. Schartl, W. Bocksch, D. H. Koschyk, W. Voelker, K. R. Karsch, J. Kreuzer, D. Hausmann, S. Beckmann, and M. Gross Use of Intravascular Ultrasound to Compare Effects of Different Strategies of Lipid-Lowering Therapy on Plaque Volume and Composition in Patients With Coronary Artery Disease Circulation, July 24, 2001; 104(4): 387 - 392. [Abstract] [Full Text] [PDF]
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R. Corti, Z. A. Fayad, V. Fuster, S. G. Worthley, G. Helft, J. Chesebro, M. Mercuri, and J. J. Badimon Effects of Lipid-Lowering by Simvastatin on Human Atherosclerotic Lesions: A Longitudinal Study by High-Resolution, Noninvasive Magnetic Resonance Imaging Circulation, July 17, 2001; 104(3): 249 - 252. [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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L. J. Feldman, M. Mazighi, A. Scheuble, J.-F. Deux, E. De Benedetti, C. Badier-Commander, E. Brambilla, D. Henin, P. G. Steg, and M.-P. Jacob Differential Expression of Matrix Metalloproteinases After Stent Implantation and Balloon Angioplasty in the Hypercholesterolemic Rabbit Circulation, June 26, 2001; 103(25): 3117 - 3122. [Abstract] [Full Text] [PDF]
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H. Kataoka, N. Kume, S. Miyamoto, M. Minami, M. Morimoto, K. Hayashida, N. Hashimoto, and T. Kita Oxidized LDL Modulates Bax/Bcl-2 Through the Lectinlike Ox-LDL Receptor-1 in Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, June 1, 2001; 21(6): 955 - 960. [Abstract] [Full Text] [PDF]
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