Studies on the initiation of atherosclerosis

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We have been continuing to isolate receptor for oxidized LDL from mouse peritoneal macrophages. However materials obtained from mouse were quite limited. Therefore we changed the souse from mouse to rabbit and isolated peritoneal macrophages and Kupffer cell and characterized receptors for oxidized LDL from there cells. Cross competition analysis between acetyl and oxidized LDL indicated that rabbit macrophages have two kinds of modified LDL receptors ; one is specific for acetyl-LDL and the other recognizes both oxidized and acetyl-LDL. On the other hand, Kupffer cells have receptor which recognizes oxidized LDL specifically. Its molecular weight is approximately 140KDa. We are now isolating this protein. However, specific receptor for acetyl-LDL does not exist in Kupffer calls.We found that not only LDL particles but also HDL particles were oxidized by Cu^<++>. Oxidized HDL showed a lessened effect on the decrease of cholesteryl ester in foam cells because of the denaturation of apo … More A-1 in HDL particles (PNAS 1991 88 p.6457). Recently we incubated HDL particles with smoke-extracts and checked their property of cholesteryl-ester efflux from macrophages-derived foam cells. Whenever HDL particles, especially apo A-1, are modified by smoke extracts. they loss the activity of cholesteryl-ester efflux from foam cells. Therefore these results indicated that apo A-1 in HDL particles is essential for efflux of cholesteryl ester in foam cells.Finally it is showed that one of the componints of oxidized LDL, lyso-phosphatidyl-choline, induced the expression of macrophage-chemotaxitic protein-1 (MOP-1) mRNA in endothelial cells. In addition as reported by Kume et al,we conformed that lyso-phosphatidyl-choline induced the gene expression of ICAM-U mRNA in endothelial cells. However time course and dose dependency of lyso-phosphatidyl-choline for the expression of both MCP-1 mRNA and ICAM-1 mRNA are quite different. Therefore the detail mechanism of these events are currently under-investigating. Less