抗酸化物質と動脈硬化

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  • Antioxidants and Atherosclerosis

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Atherosclerosis is principal contributor to the pathogenesis of myocardial and cerebral infarction, gangrene and loss of function in the extremities. The lesion result from an excessive inflammatoryfibrous proliferative response to various forms of insult to the endothelium and smooth muscle cell has been known as “response to injury hypothesis of atherosclerosis”. In recent years a large number of types of toxic injury and diseases has been linked with free radical-mediated disturbances. In many cases, implication has been that the free radical disturbance is causative in relation to the ensuing cell or tissue damage. LDL can be oxidatively modified via a free-radical mediated process. Oxidixzed LDL (ox-LDL) is a key component in endothelial injury. Once ox-LDL is formed, ox-LDL may directly injure the endothelium and play and initial role in the increased adherence and migration of monocytes and T-lymphocytes into the subendothelial space. The earliest recognizable lesion of atherosclerosis is the so-called fatty streak an aggregation of lipid-rich macrophages and T-lymphocytes within the innermost layer of the artery wall, the intima. As one of the cause of the endothelial injury, has been linked with free radical mediated alteration of low density lipoprotein (LDL), i. e., peroxidized LDL. Ox-LDL is a key compornent in endothelial injury which increased adherence of monocyte/macrophage and T-lymphocytes. The macrophages scavenge the ox-LDL and become large foam cells which accumulate in fatty streak. Lack of antioxidants participate ox-LDL formation and endothelial dysfunction. Ascorbic acid is most strong antioxidant in the tissue. The principle pathway of ascorbic acid oxidation and turnover is believed to involve the removal of two electron in succession, yielding firstly the ascorbate free radical (AFR) and then dehydroascorbate. AFR may be reduced by a micorosomal NADH dependent enzyme, monodehydro-L-ascorbate oxidase to ascorbate. Dehydroascorbate also reduced to ascorbate as shown in Fig. 1. Thus, ascorbic acid acts as redox or antioxidant as a biological role in hydrophobic state. We have reported ascorbic acid deficiency, scurvy induced not only endothelium injury of the capillary but also of the aorta in guinea pig as shown in Fig. 2. Scurvy also induced an increase in serum lipoproteins in guinea pig due to suppressed lipoprotein lipase activity and reduced cofactor for 7α-hydroxylase which is rate limiting enzyme in the process of cholesterol to bile acid metabolism. Marginal vitamin C deficiency for 8 weeks induced fatty streak without supplemental cholesterol feeding in guinea pig. Recently, scurvy prone osteo-dystrophic rat (ODS-rat) with lack of L-gulonolactone-α-oxidase was separated (Fig. 3). Kawai et al, reported that mutant cDNA of the rat has a single base mutation from guanosine (G) to adenine (A) at nucleotide 182, which mutation alters the 61st amino acid residue from cysteine to tyrosine. In the serum of the ODS-rat, we could not find apparent changes of serum lipids but found significant increase in oxidized lipid estimated as MDA (malon dialdehyde) and LPO (lipo-peroxide) as shown in Fig. 4. By electone microscopic observation of the ODS-rat aorta, we found several cells which might be macrophage or lymphocyte with vacuolar structure in the cytoplasma in subendothelial space (Fig. 5). The importance of ox-LDL in atherosclerosis was established through the use of the antioxidant, probucol, in studies of a genetic hyperlipidaemic rabbit as model of atherosclerosis. As a rosis. Numerous antioxidants have listed in Table 1. Vitamin C and E act synergistically, vitamin E act as the primary antioxidant and the resulting vitamin E radical then reacting with vatamin C to regenerate vitamin E. Still a question remains whether such an interaction between vitamin C and vatamin E radical can take place in biological systems. Niki revealed that vitamin C located in the aqueous region c

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