Study for the mechanism of LDL modification search for its inhibitor.

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One of the characteristic events in the early lesions of atherosclerosis is the accumulation of lipid-laden foam cells. Recent studies have demonstrated that most of the foam cells are derived from monocute-macrophages. These macrophages accumulate lipids in their cytoplasms, most of which are derived from low density lipoproteins (LDL). Because these cells express very few number of classical LDL receptor, the mechanism of LDL incorporation into macrophages has been a focus of extensive investigation.Goldstein et al. reported that LDL modified chemically by acetylation can be recognized and incorporated by a receptor on macrophages and they named it acetyl-LDL receptor. However, it seems unlikely that such acetylation of LDL would occur in vivo. Therefore, several investigators have been studying what are modified forms of LDL in vivo. Endothelial cell modified LDL, oxidized LDL and cigarette smoke modified LDL are now proposed as a candidate for naturally occurring modified LDL. And … More recently there are lots of evidences that endothelial cell modified LDL is as same as oxidized LDL. Parthasarathy have observed in vitro that LDL converted by chemical oxidation with Cu^<++> or Fe^<++> into a negatively-charged form transforms macrophages into foam cells and suggested that the uptake mechanism of this oxidized LDL by macrophages is mediated by the acetyl-LDL receptor. However in our previous study, we found that acetyl-LDL inhibited the degradation of [^<125>I]oxidized LDL by macrophages only by 55 %. This result has led us to postulate that the uptake mechanisms of the two lipoproteins may be different. 0ur current study was undertaken to examine the above hypothesis by comparing the binding properties of oxidized LDL, cigarette-smoke modified LDL and acetyl-LDL to macrophages. To this, we have performed competition and cross-competition in binding and degradation in macrophages. The results clearly showed that the macrophage receptors for modified LDL are composed of at least three distinct receptors with different specificities. Two of them are specific for those three LDL and the rest is a common receptor for both oxidized and cigarette smoke modified LDL, and acetyl-LDL. In the process of modifying LDL by Cu^<++>, Fe^<++> or cigarette extract, we found that superoxide anion (O_2) played an important role for modification and super-oxide dismutase (SOD) inhibited those reactions. However catalase could not prevent the modification of LDL. Therefore, in stead of S.O.D., we screened out several agents as an antioxidant, such as probucol, vitamin E or vitamin C derivatives.Probucol, so far, is an only agents which could prevent the modification of LDL. Other agents could not prevent those reaction because those could not be included into LDL particles. We next performed in vivo experiment to ask antiatherogenic activity of probucol as an antioxidant using WHHL-rabbits. When rabbits were fed 1 % probucol diet for 17 months since they were 2 month of age, the surface area of atheromatous lesion in aorta was 23 % in comparison with that of 93 % in control WHHL-rabbit. Even when rabbits were fed 1 % probucol diet at 8 month of age when their surface area of lesion was 54 %, 6 month later their lesion became about 38 % on an average. Those date indicated that oxidized LDL is one of the candidate modified LDL in vivo and probucol has a strong antiatherogenic effect. Less