The expression of matrix degrading enzymes by macrophages and macrophage-derived foam cells in atherosclerotic lesions has been proposed as a mechanism for the release of matrixbound growth factors and plaque destabilization. In this regard, macrophage plasminogen activation plays a central role in extracellular matrix degradation. Plasmin degrades several components of the extracellular matrix and activates a family of matrix-degrading metallo-proteinases. Macrophages localize and regulate plasminogen activation by their expression of a receptor for urokinase-type plasminogen activator (uPA) and several receptors for plasmin (ogen). The identities and regulation of these plasminogen receptors are not completely understood. In preliminary studies, we have demonstrated that annexin II is a constitutive plasmin receptor on murine macrophages and human monocyte-derived macrophages. In addition, we have demonstrated that autoproteolysis of membrane-bound plasmin is another mechanism by which pericellular plasmin is regulated. Following its activation, membrane-bound plasmin is proteolyzed into fragments with disparate physiologic properties. Partial NH2- terminal sequence of an enzymatically inactive 48 kDa plamin fragment, found in macrophage conditioned media and bound to cells, indicates that it comprises the entire sequence of angiostatin, a recently described inhibitor of endothelial cell proliferation and angiogenesis. The overall aims of studies proposed in this application are to: determine the regulation of pericellular proteolysis of plasmin and its consequences on macrophage function; determine whether proteolysis of membrane-bound plasmin generates fragments of plasmin expressing angiostatin activity; characterize macrophage and foam cell plasminogen receptors; and correlate aortic uPA and uPA receptor expression with lesion development in apoE-deficient mice. Result of these studies will help to elucidate the mechanisms by which macrophages orchestrate tissue remodeling and may provide us with novel interventional strategies for the treatment of atherosclerosis.
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