Increased secretion of tissue inhibitors of metalloproteinases 1 and 2 from the aortas of cholesterol fed rabbits partially counterbalances increasedmetalloproteinase activity

The balance between matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) plays an important role in extracellular matrix turnover an d thereby modulates atherosclerotic plaque development. MMP-1, -2, -3, and -9 activity is increased by atherosclerosis, but the status of TIMPs is les s clear. We therefore compared secretion of TIMPs-1 and -2 from cultured ao rtic explants derived from arch, middle, and distal portions of thoracic ao rtas of normal rabbits and rabbits fed a 1% cholesterol diet for 8 weeks, u sing reverse zymography of conditioned media. Cholesterol feeding significa ntly increased secretion of TIMP-1 from arch and middle portions (both 2.6- fold), accompanied by 2.0- and 2.7-fold increases in TIMP-2, respectively. Atherosclerotic aortas exhibited increased immunoreactive TIMP-1 and TIMP-2 in endothelial cells, smooth muscle cells, and macrophages. Staining of ex tracellular matrix was also prominent within the noncellular boundary regio n between fibrous cap and the lipid core, and within the lipid core. Increa sed TIMP-2 staining was also found in the media subjacent to the lipid core . In situ gelatin zymography demonstrated excess MMP activity within the pl aque with partial inhibition in the lipid core base and subjacent media, co nsistent with the distribution of TIMPs. Casein zymography and in situ zymo graphy demonstrated that increased caseinolytic activity was confined to th e pericellular zones of macrophages within the lipid core, again consistent with its restriction by TIMPs. In summary, atherosclerosis increases TIMP expression, which counterbalances, in part, increased MMP activity.