Action of vitamin E as antioxidant against oxidative modification of low density lipoprotein.

Abstract

The hypothesis that the oxidative modification of LDL is a key event for development of atherosclerosis was originally put forward to explain the recruitment of monocytes and the accumulation of lipidladen macrophage-derived foam cells in the fatty streak lesion [1]. Subsequent studies demonstrated a large number of biological properties of oxidized LDL that could make it more atherogenic than native LDL [2]. Several kinds of oxidation products in the oxidation of LDL have been identified and purified, and their biological properties investigated [3‐9]. These oxidation products contribute to the development of atherosclerotic lesions not only directly by inducing expression of binding molecules [10,11], cell growth [8,9] and monocyte chemotaxis [12‐14] but also indirectly by inducing the release of several kinds of cytokines [13,15] for which cytotoxicity of oxidized LDL is responsible. Findings which were accumulated through these studies are summarized in Scheme 1. It has been also shown that antioxidants could attenuate the effects of these oxidative modifications of LDL. Although the relative importance of these oxidative modificationsin vivo remains to be established, it is well-established in several experimental animal models that the administration of antioxidant can retard the development of early atherosclerotic lesions [16‐20]. Polyclonal and monoclonal antibodies against oxidized LDL have been established and gave positive reactions in Watanabe heritable hyperlipidemea (WHHL) rabbit and human atherosclerotic lesions [21‐27]. 1. Structural and biochemical properties of LDL A comprehensive report on the compositional properties of an LDL (e.g., lipid class, fatty acids, antioxidants) was provided by Esterbauer et al. [28,29]. LDL molecules are large spherical particles with diameter of 19‐25 nm. The main chemical composition is given in Table 1 with a schematic structure of an LDL particle. Taking an average value, each LDL particle would contain about 1600 molecules of cholesteryl ester (CE) and 170 molecules of triglyceride (TG) which form the lipophilic core. This core is surrounded by a monolayer of about 700 phospholipid molecules (mainly phosphatidylcholine, PC) and 600 molecules of free cholesterol (FC). The total number of fatty acid molecules bound in the different lipid classes of an LDL molecule is 2700 on average. Of these, about half are polyunsaturated acids (PUFAs), mainly linoleic acid with minor amounts of arachidonic acid