The possibility that increasing antioxidant intake could protect against coronary heart disease (CHD) is reviewed. The chapter also provides information regarding what ideal antioxidant intakes should be. Hypercholesterolemia is universally accepted as a major risk factor for athero-sclerosis. However, at any given concentration of plasma cholesterol, there is still great variability in the occurrence of cardiovascular events. One of the major breakthroughs in atherogenesis research has been the realization that oxidative modification of LDL may be a critically important step in the development of the atherosclerotic plaque.
The formation of foam cells from monocyte-derived macro phages in early atherosclerotic lesions is not caused by native LDL but only following modification ofLDL by various chemical reactions such as oxidation. The cholesterol-laden foam cell is a characteristic feature of the atherosclerotic lesion. The rapid uptake of oxidatively modified LDL occurs through scavenger receptors, which are not down regulated by cholesterol accumulation. Recognition of LDL by the scavenger receptor depends on alteration of key lysine residues of apolipoprotein B, which can be brought about by aldehydes produced during the spontaneous decomposition of lipid hydroperoxides. Some reports have suggested the presence of oxidatively modified LDL in plasma, but most oxidation is believed to occur in the arterial wall. There, LDL may be in a microenvironment where the antioxidants, which normally prevent lipid peroxidation, can become depleted.
All the cells of the vessel wall-endothelial cells, smooth muscle cells, macro phages, and lymphocytes-<:an modify LDL in vitro. LDL oxidation is believed to be caused by highly reactive free radicals but the nature and source of these have yet to be fully defined. Several mechanisms are likely to be involved, including transition metal ion-mediated generation of hydroxyl radicals, production of reactive oxygen species by enzymes such as myeloperoxidase and lipoxygenase, and direct modification by reactive nitrogen species. Oxidized LDL may also be atherogenic by mechanisms other than its rapid uptake into macrophages the scavenger receptor.
Oxidized forms of LDL are chemotactic for circulating macrophages and smooth muscle cells and facilitate monocyte adhesion to the endothelium and entry into the subendothelial space. Oxidized LDL is also cytotoxic toward arterial endothelial cells and inhibits the relea of nitric oxide and the resulting endothelium-dependent vasodilation. There is therefore G potential role for oxidized LDL in altering vasomotor responses, perhaps contributing tr vasospasm in diseased vessels.
In addition, oxidized LDL is immunogenic; autoantibodies against various epitopes 0: oxidized LDL have been found in human serum, and immunoglobulin (IgG) specific for epitope~ of oxidized LDL can be found in lesions. Oxidized LDL may be able to induce arterial waI.: cells to produce chemotactic factors, adhesion molecules, cytokine, and growth factors tha· have an important role in the development of the plaque.
Evidence for LDL oxidation in vivo is now well established. In immunocyto-chemical studies, antibodies against oxidized LDL stain atherosclerotic lesions but not normal arterial tissue. LDL extracted from animal and human lesions has been shown to be oxidized and is rapidly ta~€n up by macrophage scavenger receptor. In young myocardial infarction (MI survivors, an association has been demonstrated between increased susceptibility of LDL to oxidation and the degree of coronary atherosclerosis, while the presence of ceroid, a product of lipid peroxidation, has been shown in advanced atherosclerotic plaques. A recent study, however, has suggested that atherosclerotic plaques contain very little oxidized LDL compared to the amounts of activated complement and enzymatically altered LDL an observation that requires further study.
