Extracellular matrix remodeling mediated by leukocytes and smooth muscle cells infiltrating the vessel wall is believed to play an important role in the pathogenesis of atherosclerosis. Elucidation of the proteolytic enzymes involved in this process is crucial to the understanding and perhaps therapy of vascular diseases. The cysteine proteases cathepsins S and K are potent elastases which can be utilized by macrophages for extracellular elastin and collagen degradation but their role in atherogenesis has not been examined. Increased expression of cathepsins S and K elastolytic activities in atherosclerotic plaques, and the recent demonstration that gamma-interferon causes vascular smooth muscle cells (SMC) to express and secrete cathepsin S and further degrade extracellular elastin, lead to the hypothesis that these enzymes contribute to cellular infiltration and matrix remodeling in vascular disease. To address this hypothesis, two specific aims are proposed: 1) To define the regulation of expression and secretion of cathepsin S, and other elastolytic cathepsins, by vascular SMC, macrophages, and foam cells. Induction of cathepsin S expression by gamma-interferon suggests that other pro-and/or anti-inflammatory cytokines may be involved in the regulation of elastolytic cathepsin expression during atherogenesis. Thus, various cytokines and protease inhibitors will be utilized to test the expression and function of elastolytic cathepsins in several related cells including SMC, macrophages, and foam cells. 2) To test the hypothesis that macrophages and SMC expressing cathepsin S, and other elastolytic cathepsins, use these enzymes to degrade extracellular matrix proteins and migrate within vessel walls. A selective inhibitor of cathepsins S and K as well as cathepsin S """"""""knockout"""""""" mice will be used to test the hypothesis in models of acute vascular injury and atherogenesis (LDL receptor-deficient mice). Lesional and vascular wall morphology, elastase activity, and collagen and elastin content and integrity will be analyzed in these mice. Collectively, results from these aims should clarify the mechanisms which upregulate elastolytic cathepsins during atherogenesis and establish whether cathepsins S and K play a significant role in vascular wall remodeling. If so, these experiments should provide a molecular framework for drug design aimed at modulation of cysteine protease activity in the context of evolving atherosclerosis.
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