Elimination of macrophage-specific apolipoprotein E reduces diet-induced atherosclerosis in C57BL/6J male mice

Apolipoprotein (apo)E is synthesized in atherosclerotic lesions by macropha ges, however, its role in lesions is not known. Whereas apoE could exacerba te atherosclerosis by promoting macrophage uptake of cholesterol-rich lipop roteins or modulating protective inflammatory responses, it could also rest rict lesion formation by facilitating cholesterol efflux out of lesions. Th e role of apoE was examined in lethally irradiated male C57BL/6J wild-type (WT) mice that were repopulated with bone marrow cells (BMT) from either id entical C57BL/6J mice (WT+WT BMT) or C57BL/6J apoE-deficient mice (WT+E-/- BMT), This enabled us to compare normal mice with mice possessing macrophag es that did not express apoE, The participation of macrophage-derived apoE in atherosclerosis was assessed by placing the mice on an atherogenic diet, Male WT+E-/- BMT mice had significantly reduced lesion area in the aortic valves (P < 0.01) compared with male WT+WT BMT mice (similar to 22,000 vs, similar to 49,000 mu m(2)/section, respectively), Further evaluation reveal ed that plasma cholesterol, lipoprotein cholesterol distribution, and plasm a apoE were similar between the two groups, indicating that these known ris k factors did not account for the differences in lesion area, However, the two groups were distinguished by the amount of apoE: found in the lesions. ApoE antigen was expressed abundantly in WT+WT BMT lesions, whereas WT+E-/- BMT lesions contained little apoE. These findings indicate that the majori ty of apoE in lesions is synthesized locally by resident macrophages, and s uggest that locally produced apoE can promote diet-induced atherosclerosis in male wild-type mice.