(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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