Evidence for increased collagenolysis by interstitial collagenases-1 and -3 in vulnerable human atheromatous plaques

• Published in: Circulation (New York, N.Y.) Vol. 99; no. 19; pp. 2503 - 2509
• Main Authors: SUKHOVA, G. K, SCHÖNBECK, U, RABKIN, E, SCHOEN, F. J, POOLE, A. R, BILLINGHURST, R. C, LIBBY, P
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 18.05.1999; American Heart Association, Inc
• Subjects: Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Blotting, Western; Cardiology. Vascular system; Carotid Arteries - metabolism; Carotid Arteries - pathology; Collagen - metabolism; Collagenases - metabolism; Humans; Immunohistochemistry; Matrix Metalloproteinase 1; Matrix Metalloproteinase 13; Medical sciences; Rupture; Human; Immunohistochemistry; Pathophysiology; Enzyme; Cardiovascular disease; Exploration; Metalloproteins; Vascular disease; Pathology; Atherosclerotic plaque; Collagen; Morphological analysis; Atherosclerosis; Molecular biology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.99.19.2503

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. 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. 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.