|Budget Amount *help
¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1989: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 1988: ¥4,200,000 (Direct Cost: ¥4,200,000)
The foam cell has been recognized as characteristic feature of xanthomas and atheroma. Many foam cells in early atheromatous lesions share properties characteristic of the monocute derived macrophages.
Rherefore, the macrophage may be the progenitor of certain foam cells that are involved in atherosclerosis. Several investigators demonstrated in vitro that macrophages can ingest large amounts of native lipoproteins, such as beta-VLDL, WHHL-VLDL and also the certain chemically modified lipoproteins, such as acetylated LDL and malondialdehyde-treated LDL through the process of receptor mediated endocytosis and thereby they become foam cells. Yet modified LDL has, not been demonstrated to exist in the body. Recently oxidized LDL has been reported to be efficiently taken up by marophages at least in part by way of acetyl-LDL receptor. Because lipid peroxidation has been suggested to be involved in atherogenesis by pathological or epidemiological investigation, oxidized LDL is considered as
a candidate for an example of naturally occurring, modified LDL.
Recently using WHHL-rabbit, an aniihal model for familial hypercholestrolemia, we demonstrated that probucol, originally developed as an antioxidant, prevents the progression of atheromatous plaques in vivo, suggesting the existence of oxidized LDL in vivo indirectly. Therefore in this study, we investigated the precise antialtherogenoc mechanisms of probucol in vitro. First, we studied antioxidant effects of probucol. LDL isolated from WHHL-rabbit under treatment with probucbl were shown to be resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages in comparison with LDL isolated from untreated WHHL-rabbits. In the middle of experiments, we discovered the existence of specific receptor for oxidized LDL. We are now doing to purify this receptor. There is a possibility that probucol might affect the membrane of macrophage to inhibit the uptake of atherogenic lipoproteins such as beta-VLDL, acety-LDL, oxidized LDL, or cigarette smoke modified LDL, subsequently preventing the foam cell transformation of macrophages. Therefore we investigated such a possibility. However, probucol could not prevent the uptake of atherogenic lipoproteins in vitro. When macrophages become foam cells, they synthesizes several biologically active substances, such as interleukin 1, araclidonate metabolites and MDGF. These products have attracted increasing attention, since recent studies have indicated their close relation to atherogenesis. Therefore we questioned whether probucol could affect the formation of these products by macrophages, as an antiatherogenic effect. However, so far, we could not demonstrated such an effect of probucol in vitro. Less