Effect of macrophage-derived mouse apoE, human apoE3-Leiden, and human apoE2 (Arg158 -> Cys) on cholesterol levels and atherosclerosis in apoE-deficient mice

The effect of monocyte/macrophage-derived wild-type mouse apolipoprotein E (apoE), human apoE3-Leiden, and human apoE2 on serum cholesterol levels and the development of atherosclerosis in apoE-deficient (apoe-/-) mice was in vestigated by using bone marrow transplantation (BMT). At 4 weeks after BMT , murine apoe+/+ bone marrow reduced serum cholesterol levels by 87% in apo e-/- mice, whereas macrophage-derived human apoE3-Leiden and human apoE2 in duced a maximal, transient reduction of 35% and 48%, respectively. At 4 mon ths after BMT, atherosclerosis was 23-fold (P<0.001) reduced in apoe+/+-->a poe-/- mice, whereas no significant reduction in apoE3-Leiden.apoe-/--->apo e-/- and apoE2.apoe-/--->apoe-/- mice could be demonstrated. A highly signi ficant decrease in serum cholesterol levels (78% reduction) and atheroscler osis (21-fold, P<0.001) was found in apoE3-Leiden.apoe-/- animals expressin g high levels of apoE in multiple tissues, whereas apoE2 was ineffective ev en at high concentrations. Furthermore, in contrast to apoE-deficient macro phages, cholesterol efflux from apoE2 or apoE3-Leiden macrophages was not i mpaired. In conclusion, apoE3-Leiden as well as apoE2 are less effective in reducing cholesterol levels and atherosclerosis in apoe-/- animals, compar ed with apoe+/+, with apoE2<apoE3-Leiden<apoe+/+, irrespective of the obser ved adequate efflux of cholesterol from macrophages expressing apoE2 and ap oE3-Leiden, indicating that normalization of cholesterol efflux by macropha ges is not accompanied by measurable effects on lesion growth.