CIRCUMFERENTIAL STRESS AND MATRIX METALLOPROTEINASE-1 IN HUMAN CORONARY ATHEROSCLEROSIS - IMPLICATIONS FOR PLAQUE RUPTURE

Atherosclerotic plaque rupture may occur when regions of weakened extr acellular matrix are subjected to increased mechanical stresses. Since collagen is a major determinant of extracellular matrix strength, enz ymes that degrade collagen may play an important role in destabilizing the atherosclerotic lesion. To test the hypothesis that matrix metall oproteinase 1 (interstitial collagenase, or MMP-1), which initiates de gradation of fibrillar collagens, colocalizes with increased stress in the fibrous cap of the atherosclerotic lesion, 12 unruptured human co ronary lesions were studied. Finite-element analysis was used to deter mine the distribution of stress in the lesion, with estimates of mater ial properties from previous measurements of human tissues. A computer ized image analysis system was used to determine the distribution of i mmunoreactive MMP-1 within the fibrous tissue of the lesion. There was a significant correlation between immunoreactive MMP-1 and circumfere ntial 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 t wofold greater MMP-1 expression than the lowest-stress regions. In unr uptured human atherosclerotic coronary lesions, overexpression of MMP- 1 is associated with increased circumferential stress in the fibrous p laque. Degradation and weakening of the collagenous extracellular matr ix at these critical high-stress regions may play a role in the pathog enesis of plaque rupture and acute ischemic syndromes.