title: Circumferential stress and matrix metalloproteinase 1 in human coronary atherosclerosis. Implications for plaque rupture.
abstract: Atherosclerotic plaque rupture may occur when regions of weakened extracellular matrix are subjected to increased mechanical stresses. Since collagen is a major determinant of extracellular matrix strength, enzymes that degrade collagen may play an important role in destabilizing the atherosclerotic lesion. To test the hypothesis that matrix metalloproteinase 1 (interstitial collagenase, or MMP-1), which initiates degradation of fibrillar collagens, colocalizes with increased stress in the fibrous cap of the atherosclerotic lesion, 12 unruptured human coronary lesions were studied. Finite-element analysis was used to determine the distribution of stress in the lesion, with estimates of material properties from previous measurements of human tissues. A computerized image analysis system was used to determine the distribution of immunoreactive MMP-1 within the fibrous tissue of the lesion. There was a significant correlation between immunoreactive MMP-1 and circumferential tensile stress in the fibrous cap within a given lesion (median Spearman rank correlation coefficient, .36; interquartile range, -.02 to .81; P < .02). Within a given lesion, the highest-stress region had twofold greater MMP-1 expression than the lowest-stress regions. In unruptured human atherosclerotic coronary lesions, overexpression of MMP-1 is associated with increased circumferential stress in the fibrous plaque. Degradation and weakening of the collagenous extracellular matrix at these critical high-stress regions may play a role in the pathogenesis of plaque rupture and acute ischemic syndromes.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. rtlee@bics.bwh.harvard.edu
authors.forename: R T
authors.initials: RT
authors.lastname: Lee
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoen
authors.forename: H M
authors.initials: HM
authors.lastname: Loree
authors.forename: M W
authors.initials: MW
authors.lastname: Lark
authors.forename: P
authors.initials: P
authors.lastname: Libby
mesh_terms: D017364:Collagenases / Q000378:metabolism*; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000473:pathology; D003331:Coronary Vessels / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D020781:Matrix Metalloproteinase 1; D012422:Rupture, Spontaneous; D013314:Stress, Mechanical
chemical_list: D017364:Collagenases; D020781:Matrix Metalloproteinase 1