Genetically determined resistance to collagenase action augments interstitial collagen accumulation in atherosclerotic plaques.

BACKGROUND: We hypothesized that collagenolytic activity produced by activated macrophages contributes to collagen loss and the subsequent instability of atheromatous lesions, a common trigger of acute coronary syndromes. However, no direct in vivo evidence links collagenases with the regulation of collagen content in atherosclerotic plaques. METHODS AND
RESULTS: To test the hypothesis that collagenases influence the structure of atheromata, we examined collagen accumulation in atherosclerotic lesions of apolipoprotein E-deficient mice (apoE-/-) that express collagenase-resistant collagen-I (ColR/R/apoE-/-, n=12) or wild-type collagen-expressing mice (Col+/+/apoE-/-, n=12). Aortic atheromata of both groups had similar sizes and numbers of macrophages, a major source of collagenases. However, aortic intimas from ColR/R/apoE-/- mice contained fewer smooth muscle cells, a source of collagen, probably because of decreased migration or proliferation or increased cell death. Despite reduced numbers of smooth muscle cells, atheromata of ColR/R/apoE-/- mice contained significantly more intimal collagen than did those of Col+/+/apoE-/- mice.
CONCLUSIONS: These results establish that collagenase action regulates plaque collagen turnover and smooth muscle cell accumulation.