Atherosclerosis The Road Ahead

Serum cholesterol is carried by several lipoprotein parti-Medicine and Atherosclerosis cles that perform the complex physiologic tasks of * Department of Medicine transporting dietary and endogenously produced lipids Division of Endocrinology and Metabolism (reviewed in Witztum and Steinberg, 1995). Chylomicrons † Department of Cellular and Molecular Medicine provide the primary means of transport of dietary lipids, while very low density lipoproteins (VLDL), low density 9500 Gilman Drive lipoproteins (LDL), and high density lipoproteins (HDL) La Jolla, California 92093 function to transport endogenous lipids. Triglyceride-rich VLDL particles containing apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E) are synthesized by the liver and function to transport fatty acids to adi-Complications of atherosclerosis are the most common pose tissue and muscle. After triglyceride removal in causes of death in Western societies. In broad outline, peripheral tissues, a portion of the remaining VLDL rem-atherosclerosis can be considered to be a form of nants are metabolized to LDL particles by further re-chronic inflammation resulting from interaction between moval of core triglycerides and dissociation of apolipo-modified lipoproteins, monocyte-derived macrophages, proteins other than apo B-100. In humans, the majority T cells, and the normal cellular elements of the arterial of serum cholesterol is carried by LDL particles. wall. This inflammatory process can ultimately lead to While LDL has an essential physiological role as a the development of complex lesions, or plaques, that vehicle for the delivery of cholesterol to peripheral tis-protrude into the arterial lumen. Plaque rupture and sues, increased LDL cholesterol levels are associated thrombosis results in the acute clinical complications of with increased risk of cardiovascular disease. LDL is myocardial infarction and stroke (Navab et al., 1996; taken up by cells via LDL receptors that recognize an Ross, 1999; Steinberg and Witztum, 1999). Among the N-terminal domain of apo B-100. The circulating level many genetic and environmental risk factors that have of LDL is determined in large part by its rate of uptake been identified by epidemiologic studies (Table 1), elevated levels of serum cholesterol are probably unique through the hepatic LDL receptor pathway, as evi-in being sufficient to drive the development of athero-denced by the fact that lack of functional LDL receptors sclerosis in humans and experimental animals, even in is responsible for the massive accumulation of LDL in the absence of other known risk factors. The elucidation patients with homozygous familial hypercholesterol-of molecular mechanisms that control cholesterol bio-emia (Goldstein and Brown, 1977). …