Modification of LDL structure in relation to atherosclerosis

Incubation of monocyte/macrophages with even very high concentrations of native LDL fails to lead to cholesterol accumulation, yet LDL is the ultimate source of the cholesterol accumulating in monocyte-derived foam cells. This apparent paradox has been resolved by the demonstration that a number of modifications of LDL result in forms that are taken up more rapidly by the macrophage. The best studied of these modifications is oxidation and there is a large body of evidence from animal studies showing that oxidative modification occurs in vivo. Furthermore, inhibition of oxidative modification in animal models slows the progression of early lesions. Epidemiologic studies show a negative correlation between intake of antioxidant vitamins and risk of coronary heart disease but we do not know whether this reflects a causal relationship. Clinical intervention studies are already underway but it may be some 5-10 years before we have a clear answer. Other modifications of LDL that increase its uptake by monocyte/macrophages include self-aggregation and complexing with autoantibodies. These and other modifications may be fully as important as oxidative modification but research in these areas has still not progressed to the point of intervention in animal models let alone to the level of clinical investigation.