Evidence has accumulated in recent years to implicate the macrophage derived foam cell as a key actor in atherogenesis. Further, it has been shown that mouse peritoneal and human blood-derived macrophages possess receptor-mediated endocytotic mechanisms that allow them to take up plasma lipoproteins in a manner producing foam cells in vitro. It thus appears that macrophage/foam cells play a major role in atherogenesis. We hypothesize that the uptake of various forms of altered lipoproteins triggers developing macrophage/foam cells to secrete products that initiate and perpetuate inflammatory vascular tissue injury leading to the development of mature atherosclerotic plaques. There are three aspects of in vitro macrophage/foam cell conversion that we intend to explore in the present application: (1) We intend to study the possibility that distinct lipoprotein subspecies, particularly certain subspecies, of low density lipoproteins, alone or complexed to highly sulfated proteoglycans derived from the arterial wall, are taken up by macrophages to form foam cells during atherogenesis. (2) Since little is known about the role of macrophage/foam cell secretory products in atherogenesis, we propose to identify, and in certain instances isolate, the secretory products of macrophages and foam cells triggered in culture via well characterized pathways (e.g. acetyl-LDL and maleylated albumin) and compare these with secretory products triggered by pathways defined in (1) above. Particular attention will be given to four classes of secretory products: highly sulfated proteoglycans, neutral proteases (especially plasminogen activator), oxygen radicals and prostaglandins. (3) Finally, we will investigate the possible modification of LDL subspecies by secretory products of macrophage/foam cells, such as serine proteases, and the result of this modification on subspecies uptake by the macrophage. The rationale is that, under certain conditions to be defined in goals (1) and (2), there may be a cyclic feedback process that enhances the tendency for macrophages to produce foam cells and/or damaging secretory products.
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