An A+ for macrophages in reducing atherosclerosis?

Epidemiological studies within developed populations have demonstrated that high levels of HDL cholesterol are associated with decreased risk of atherosclerotic cardiovascular disease, although the precise mechanism for this protective effect is not completely understood. Apolipoprotein (apo) AI is the major protein constituent of HDL, and high-level hepatic production of human apoAI in transgenic mice leads not only to increased HDL cholesterol levels and a human-like polydisperse HDL profile, but also to a reduction of atherosclerosis in these mice, which is induced by feeding a high-cholesterol cholic acid–containing diet.1–3 Furthermore, breeding these apoAI transgenics onto the apoE-deficient background also substantially reduces spontaneous atherosclerosis in mice fed a low-fat chow diet.4,5 Similarly, recombinant adenovirus–mediated expression of apoAI also decreases lesion progression in apoE-deficient mice and has been found to lead to lesion regression in LDL receptor–deficient mice.6,7 Since the earliest cellular lesion of atherosclerosis consists of cholesterol-loaded macrophagederived foam cells, much attention has been paid to the role of macrophages, and to macrophage cholesterol metabolism, in atherogenesis. A seminal role for macrophages in atherogenesis has been demonstrated by the marked reduction of atherosclerosis in several mouse models with disruptions of macrophage cytokines, chemokines, or their receptors,8–10 and of adhesion molecules responsible for macrophage binding to and crossing the arterial endothelium.11,12 Macrophages synthesize and secrete apoE, which can act as a cholesterol acceptor to remove cholesterol from cholesterol loaded cells through the activity of the ABCA1 transporter.13–16