Physiological expression of macrophage apoE in the artery wall reduces atherosclerosis in severely hyperlipidemic mice

We have previously reported that the introduction of macrophage apoE into mice lacking both apoE and the LDL receptor (apoE^-/-/LDLR^-/-) through bone marrow transplantation (apoE^+/+/LDLR^-/-→apoE^-/-/ LDLR^-/-) produces progressive accumulation of apoE in plasma without affecting lipid levels. This model provides a tool to study the effects of physiologically regulated amounts of macrophage apoE on atherogenesis in hyperlipidemic animals. Ten-week-old male apoE^-/-/LDLR^-/- mice were transplanted with either apoE^+/+/LDLR^-/- (n = 11) or apoE^-/-/LDLR^-/- (n = 14) marrow. Although there were no differences between the two groups in lipid levels at baseline or at 5 and 9 weeks after transplantation, apoE levels in the apoE^+/+LDLR^-/-→apoE^-/-/ LDLR^-/- mice increased to 4 times the apoE levels of normal mice. This resulted in a 60% decrease in aortic atherosclerosis in the apoE^+/+/LDLR^-/-→apoE^-/-/ LDLR^-/- compared with the apoE^-/-/LDLR^-/-→apoE^-/-/ LDLR^-/- controls, (15,957 ± 1907 vs. 40,115 ± 8302 μm² ± SEM, respectively). In a separate experiment, apoE^+/+/LDLR^-/- mice were transplanted with either apoE^+/+/LDLR^-/- or apoE^-/-/LDLR^-/- marrow and placed on a high-fat diet for 8 weeks. In the absence of macrophage apoE, lesion area was increased by 75% in the aortic sinus and by 56% in the distal aorta. These data show that physiologic levels of macrophage apoE in the vessel wall are anti-atherogenic in conditions of severe hyperlipidemia and can affect later stages of plaque development.