MACROPHAGE PROTEASE CASCADE AND VASCULAR REMODELING

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DESCRIPTION (Adapted from Investigator's Abstract): Expression of matrix-degrading proteases by macrophages may effect atherosclerotic lesion development through the release of matrix-bound growth factors and plaque destabilization. In this regard, macrophage expression of urokinase-type plasminogen activator (uPA) and subsequent plasminogen activation plays a central role in matrix degradation. Plasmin degrades matrix components and deactivates matrix-degrading metalloproteinases (MMP). Regulation of this protease cascade is the subject of this continuing grant application. The aims of this proposal are to: 1) Determine the cooperative role of macrophage uPA and MMP expression in tissue remodeling and release of matrix-bound growth factors. 2) Determine the role of extracellular matrix in the regulation of macrophage uPA and MMP expression. Matrix components, cellular receptors and signal transduction pathways that mediate matrix-induction of uPA and MMP will be identified. The mechanism by which MMP regulate matrix-induction of macrophage uPA expression will be determined. 3) Determine the role of TGF-beta in macrophage mediated tissue remodeling. Monocyte differentiation-dependent TGF-beta receptor expression will be characterized and correlated with TGF-beta induced alterations in uPA and MMP expression. The role of differential TFG-beta receptor expression in macrophage uPA and MMP expression will be determined utilizing cells transfected with wild type and mutant type I and II receptors. 4) Determine the role of annexin II in the regulation of pericellular plasmin activity. The role of cell surface annexin II in the regulation of plasmin autoproteolysis and formation of kringle containing fragments will be determined utilizing cells transfected with wild type and mutant annexin II. The role of autoproteolysis in the regulation of macrophage transmigration, matrix degradation and release of matrix-bound growth factors will be determined. Results of these studies will help elucidate the mechanisms by which macrophages orchestrate matrix degradation and provide us with novel interventional strategies for the treatment of atherosclerosis and other chronic inflammatory diseases.