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Dysregulated extracellular matrix (ECM) metabolism may contribute to vascular remodeling during the development and complication of human atherosclerotic lesions. We in- vestigated the expression of matrix metalloproteinases (MMPs), a family of enzymes that degrade ECM compo- nents in human atherosclerotic plaques (n =30) and in uninvolved arterial specimens (n=11). We studied members of all three MMP classes (interstitial coilagenase, MMP-1; gel- atinases, MMP-2 and MMP-9; and stromelysin, MMP-3) and their endogenous inhibitors (TIMPs 1 and 2) by immu- nocytochemistry, zymography, and immunoprecipitation. Normal arteries stained uniformly for 72-kD gelatinase and TIMPs. In contrast, plaques' shoulders and regions of foam cell accumulation displayed locally increased expression of 92-kD gelatinase, stromelysin, and interstitial collagenase. However, the mere presence of MMP does not establish their catalytic capacity, as the zymogens lack activity, and TIMPs may block activated MMPs. All plaque extracts con- tained activated forms of gelatinases determined zymo- graphically and by degradation of 3H-collagen type IV. To test directly whether atheromata actually contain active ma- trix-degrading enzymes in situ, we devised a method which allows the detection and microscopic localization of MMP enzymatic activity directly in tissue sections. In situ zymog- raphy revealed gelatinolytic and caseinolytic activity in fro- zen sections of atherosclerotic but not of uninvolved arterial tissues. The MMP inhibitors, EDTA and 1,10-phenanthroline, as well as recombinant TIMP-1, reduced these activities which colocalized with regions of increased immunoreactive MMP expression, i.e., the shoulders, core, and microvascula- ture of the plaques. Focal overexpression of activated MMP may promote destabilization and complication of atherosclerotic plaques and provide novel targets for therapeutic in- tervention. (
Galis et al. (Thu,) studied this question.