Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity.

Abstract

There is no longer any doubt that high plasma levels of LDL are atherogenic and that lowering them can reduce the risk of coronary heart disease, but the specific events induced by high levels of LDL in the artery wall are only now being elucidated. Once these processes are understood, we may find that there are ways to intervene at the level. Recent advances have brought us closer to being able to do this with regard to the uptake of LDL by macrophages and the development of the fattty streak, the earliest lesion in atherogenesis. Studies both in vitro and in vivo support the hypothesis that LDL undergoes an oxidative modification that targets it for uptake by the macrophage through a specific receptor - the acetyl LDL or scavenger receptor. Intervention studies in the LDL receptor-deficient animal model for atherosclerosis (the WHHL rabbit), using probucol as an antioxidant, show that the progression of the fatty streak can be slowed under conditions that do not lower plasma cholesterol levels. Much more remains to be done to establish the clinical relevance of these findings. Nevertheless, the experimental data available to date encourage aggressive additional research on the oxidative modification of LDL. This review has emphasized the oxidative modification of LDL because the evidence for its occurrence in vivo and for its role in atherogenesis is already persuasive. However, we recognize that with further study additional modifications may prove to be equally important or even more important. For example, the glycation of LDL may help explain the increased susceptibility of diabetic subjects to atherosclerotic complications. If so, rigid control of hyperglycemia may reduce such complications. As we learn more about these and other postsecretory modifications of LDL, we can hope to find ways of preventing them. To the extent that modifications of these kinds play an important part in atherogenesis, we may be able to intervene and obtain protection beyond that obtained by lowering plasma LDL levels.