(Circulation. 1999;99:2503-2509.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Evidence for Increased Collagenolysis by Interstitial Collagenases-1 and -3 in Vulnerable Human Atheromatous Plaques
From the Vascular Medicine and Atherosclerosis Unit, Cardiovascular Division, Department of Medicine (G.K.S., U.S., P.L.), and Department of Pathology (E.R., F.J.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, Mass; Joint Diseases Laboratory (A.R.P.), Shriners Hospitals for Children, Division of Surgical Research, Department of Surgery, McGill University, Montreal, Quebec, Canada; and Department of Clinical Sciences (R.C.B.), Colorado State University, Fort Collins, Colo.
Correspondence to Peter Libby, MD, 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—Several recent studies attempted to classify plaques as those prone to cause clinical manifestations (vulnerable, atheromatous plaques) or those less frequently associated with acute thrombotic complication (stable, fibrous plaques). Defining the cellular and molecular mechanisms that underlie these morphological features remains a challenge. Because interstitial forms of collagen determine the biomechanical strength of the atherosclerotic lesion, this study investigated expression of the collagen-degrading matrix metalloproteinase (MMP) interstitial collagenase-3 (MMP-13) and the previously studied MMP-1 in human atheroma and used a novel technique to test the hypothesis that collagenolysis in atheromatous lesions exceeds that in fibrous human atherosclerotic lesions.
Methods and Results—Human carotid atherosclerotic plaques, similar in size, were separated by conventional morphological characteristics into fibrous (n=10) and atheromatous (n=10) lesions. Immunohistochemical and Western blot analysis demonstrated increased levels of MMP-1 and MMP-13 in atheromatous versus fibrous plaques. In addition, collagenase-cleaved type I collagen, demonstrated by a novel cleavage-specific antibody, colocalized with MMP-1– and MMP-13–positive macrophages. Macrophages, rather than endothelial or smooth muscle cells, expressed MMP-13 and MMP-1 on stimulation in vitro. Furthermore, Western blot analysis demonstrated loss of interstitial collagen type I and increased collagenolysis in atheromatous versus fibrous lesions. Finally, atheromatous plaques contained higher levels of proinflammatory cytokines, activators of MMPs.
Conclusions—This report demonstrates that atheromatous rather than fibrous plaques might be prone to rupture due to increased collagenolysis associated with macrophages, probably mediated by the interstitial collagenases MMP-1 and MMP-13.
Key Words: atherosclerosis • collagen • cells • enzymes
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R. S. Hundal, A. Gomez-Munoz, J. Y. Kong, B. S. Salh, A. Marotta, V. Duronio, and U. P. Steinbrecher Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels J. Biol. Chem., June 27, 2003; 278(27): 24399 - 24408. [Abstract] [Full Text] [PDF]
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S. Beyzade, S. Zhang, Y.-k. Wong, I. N. M. Day, P. Eriksson, and S. Ye Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2130 - 2137. [Abstract] [Full Text] [PDF]
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C. M. Dollery, C. A. Owen, G. K. Sukhova, A. Krettek, S. D. Shapiro, and P. Libby Neutrophil Elastase in Human Atherosclerotic Plaques: Production by Macrophages Circulation, June 10, 2003; 107(22): 2829 - 2836. [Abstract] [Full Text] [PDF]
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Z. Luan, A. J. Chase, and A. C. Newby Statins Inhibit Secretion of Metalloproteinases-1, -2, -3, and -9 From Vascular Smooth Muscle Cells and Macrophages Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 769 - 775. [Abstract] [Full Text] [PDF]
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A. Krettek, G. K. Sukhova, and P. Libby Elastogenesis in Human Arterial Disease: A Role for Macrophages in Disordered Elastin Synthesis Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 582 - 587. [Abstract] [Full Text] [PDF]
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 J. H. Von der Thusen, J. Kuiper, T. J. C. Van Berkel, and E. A. L. Biessen Interleukins in Atherosclerosis: Molecular Pathways and Therapeutic Potential Pharmacol. Rev., March 1, 2003; 55(1): 133 - 166. [Abstract] [Full Text] [PDF]
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M. W. Manning, L. A. Cassis, and A. Daugherty Differential Effects of Doxycycline, a Broad-Spectrum Matrix Metalloproteinase Inhibitor, on Angiotensin II-Induced Atherosclerosis and Abdominal Aortic Aneurysms Arterioscler Thromb Vasc Biol, March 1, 2003; 23(3): 483 - 488. [Abstract] [Full Text] [PDF]
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B. R. Kwak, N. Veillard, G. Pelli, F. Mulhaupt, R. W. James, M. Chanson, and F. Mach Reduced Connexin43 Expression Inhibits Atherosclerotic Lesion Formation in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, February 25, 2003; 107(7): 1033 - 1039. [Abstract] [Full Text] [PDF]
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D. K. Das Cardioprotection With High-Density Lipoproteins: Fact or Fiction? Circ. Res., February 21, 2003; 92(3): 258 - 260. [Full Text] [PDF]
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P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]
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V. Lemaitre, P. D. Soloway, and J. D'Armiento Increased Medial Degradation With Pseudo-Aneurysm Formation in Apolipoprotein E-Knockout Mice Deficient in Tissue Inhibitor of Metalloproteinases-1 Circulation, January 21, 2003; 107(2): 333 - 338. [Abstract] [Full Text] [PDF]
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B. Axisa, I. M. Loftus, A. R. Naylor, S. Goodall, L. Jones, P. R.F. Bell, M. M. Thompson, and C. Napoli Prospective, Randomized, Double-Blind Trial Investigating the Effect of Doxycycline on Matrix Metalloproteinase Expression Within Atherosclerotic Carotid Plaques * Editorial Comment Stroke, December 1, 2002; 33(12): 2858 - 2864. [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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 M.T. Henry, K. McMahon, A.J. Mackarel, K. Prikk, T. Sorsa, P. Maisi, R. Sepper, M.X. FitzGerald, and C.M. O'Connor Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF Eur. Respir. J., November 1, 2002; 20(5): 1220 - 1227. [Abstract] [Full Text] [PDF]
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 C. Zaragoza, E. Soria, E. Lopez, D. Browning, M. Balbin, C. Lopez-Otin, and S. Lamas Activation of the Mitogen Activated Protein Kinase Extracellular Signal-Regulated Kinase 1 and 2 by the Nitric Oxide-cGMP-cGMP-Dependent Protein Kinase Axis Regulates the Expression of Matrix Metalloproteinase 13 in Vascular Endothelial Cells Mol. Pharmacol., October 1, 2002; 62(4): 927 - 935. [Abstract] [Full Text] [PDF]
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G. Ghilardi, M. L. Biondi, M. DeMonti, O. Turri, E. Guagnellini, and R. Scorza Matrix Metalloproteinase-1 and Matrix Metalloproteinase-3 Gene Promoter Polymorphisms Are Associated With Carotid Artery Stenosis Stroke, October 1, 2002; 33(10): 2408 - 2412. [Abstract] [Full Text] [PDF]
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T. Cyrus, S. Sung, L. Zhao, C. D. Funk, S. Tang, and D. Pratico Effect of Low-Dose Aspirin on Vascular Inflammation, Plaque Stability, and Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice Circulation, September 3, 2002; 106(10): 1282 - 1287. [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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U. Schonbeck, G. K. Sukhova, N. Gerdes, and P. Libby TH2 Predominant Immune Responses Prevail in Human Abdominal Aortic Aneurysm Am. J. Pathol., August 1, 2002; 161(2): 499 - 506. [Abstract] [Full Text] [PDF]
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 C. Muckian, A. Fitzgerald, A. O'Neill, A. O'Byrne, D. J. Fitzgerald, and D. C. Shields Genetic variability in the extracellular matrix as a determinant of cardiovascular risk: association of type III collagen COL3A1 polymorphisms with coronary artery disease Blood, July 30, 2002; 100(4): 1220 - 1223. [Abstract] [Full Text] [PDF]
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S. Hussain, J. W. Assender, M. Bond, L.-F. Wong, D. Murphy, and A. C. Newby Activation of Protein Kinase Czeta Is Essential for Cytokine-induced Metalloproteinase-1, -3, and -9 Secretion from Rabbit Smooth Muscle Cells and Inhibits Proliferation J. Biol. Chem., July 19, 2002; 277(30): 27345 - 27352. [Abstract] [Full Text] [PDF]
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C. Buono, C. E. Come, J. L. Witztum, G. F. Maguire, P. W. Connelly, M. Carroll, and A. H. Lichtman Influence of C3 Deficiency on Atherosclerosis Circulation, June 25, 2002; 105(25): 3025 - 3031. [Abstract] [Full Text] [PDF]
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J. A. Ardans, A. P. Economou, J. M. Martinson Jr., M. Zhou, and L. M. Wahl Oxidized low-density and high-density lipoproteins regulate the production of matrix metalloproteinase-1 and -9 by activated monocytes J. Leukoc. Biol., June 1, 2002; 71(6): 1012 - 1018. [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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A. J. Chase, M. Bond, M. F. Crook, and A. C. Newby Role of Nuclear Factor-{kappa}B Activation in Metalloproteinase-1, -3, and -9 Secretion by Human Macrophages In Vitro and Rabbit Foam Cells Produced In Vivo Arterioscler Thromb Vasc Biol, May 1, 2002; 22(5): 765 - 771. [Abstract] [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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 N. Gerdes, G. K. Sukhova, P. Libby, R. S. Reynolds, J. L. Young, and U. Schonbeck Expression of Interleukin (IL)-18 and Functional IL-18 Receptor on Human Vascular Endothelial Cells, Smooth Muscle Cells, and Macrophages: Implications for Atherogenesis J. Exp. Med., January 22, 2002; 195(2): 245 - 257. [Abstract] [Full Text] [PDF]
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