Apolipoprotein E and Coronary Disease: A Puzzling Paradox

A polipoprotein E (apoE) has effects on lipoprotein metabolism and the vasculature that have long been considered to be anti-atherogenic [1]. In the plasma, apoE is found on the surface of triglyceride-rich lipoproteins, such as very low density lipoproteins (VLDL) and remnant particles. ApoE is also found on high density lipoproteins (HDL) and as such may serve distinct functions depending on its specifi c lipoprotein association. ApoE is the main ligand for clearance of triglyceride rich particles via the low density lipoprotein receptor (LDLR) and related receptors in the liver, thereby regulating plasma levels of these lipoproteins and thus also of plasma cholesterol and triglyceride levels. In mice, apoE gene deletion results in severe hypercholesterolemia, due to accumulation of VLDL and remnant particles, and in accelerated atherosclerosis. In humans, there are two common apoE polymorphisms, apoE2 and apoE4, that affect its function compared with the wild-type apoE3 and that have been extensively studied (sidebar) [2]. While these common genetic variants of apoE clearly affect lipoprotein metabolism and risk of atherosclerosis, they account for only a limited portion of the variability in plasma apoE levels. ApoE is believed to have additional properties beyond regulation of lipoprotein remnant clearance that have been historically considered anti-atherogenic in nature [3]. For example, in LDLR-defi cient mice, hepatic overexpression of apoE was shown to induce regression of atherosclerosis without affecting plasma lipoprotein levels [4]. Extrahepatic apoE expression has been shown to inhibit atherosclerosis in otherwise apoE-defi cient mice without infl uencing cholesterol levels [5,6]. Additional potentially anti-atherogenic properties of apoE include promotion of macrophage cholesterol effl ux [7], inhibition of T cell [8] and vascular smooth muscle cell [9] proliferation, and antioxidant effects [10]. Furthermore, apoE reduces the infl ammatory response during experimental endotoxemia in mice [11,12], supporting a role for apoE in limiting innate infl ammatory responses to exogenous antigens. The mechanisms for many of the pleitropic effects are not well understood. Nevertheless, based on these properties, apoE has been widely considered to be anti-atherogenic [3]. In this context, Mooijaart and colleagues present novel data in PLoS Medicine that should stimulate more intense examination of the role of apoE in human atherosclerosis [13]. They report, for the fi rst time, a surprising positive relationship between plasma apoE levels and cardiovascular mortality. They used the Leiden 85-plus Study, a prospective study of 546 elderly people over the age of 85 at time of recruitment and …