EXPRESSION OF TISSUE INHIBITOR OF METALLOPROTEINASES-3 IN HUMAN ATHEROMA AND REGULATION IN LESION-ASSOCIATED CELLS - A POTENTIAL PROTECTIVEMECHANISM IN PLAQUE STABILITY

Atherosclerotic plaque stability depends on the structural integrity o f its extracellular matrix skeleton. The balance between degradation b y matrix metalloproteinases (MMPs) and tissue inhibitors of metallopro teinases (TIMPs) may regulate plaque stability. Although MMP expressio n in atheroma is well documented, localization and control of expressi on of TIMPs in these lesions is incomplete. Extracts of atheroma (n=14 ) had 5-fold higher levels of TIMP-3 than nonatherosclerotic tissue (n =10). Plaques (n=24) contained abundant TIMP-1, -2, and -3 in macropha ges in plaque shoulders, intimal-medial borders, and areas overlying t he lipid core, as well as in medial smooth muscle cells, albeit in les ser amounts. These observations suggested that macrophages, a cell typ e not heretofore known to express TIMP-3, did so in atheroma in vivo. Further studies in vitro established the human macrophage as a novel s ource of TIMP-3 mRNA and protein. Human smooth muscle cells constituti vely expressed TIMP-1, -2 and -3 proteins; platelet-derived growth fac tor and transforming growth factor-beta augmented levels of TIMP-1 and TIMP-3 but not TIMP-2. These findings suggest that regulated expressi on of TIMP-3, in addition to the presence of TLMP-1 and TIMP-2, counte racts MMP activity in atheroma and hence influences plaque stability.