Apolipoprotein E (
apoE) and the
low density lipoprotein receptor (LDLr) are well recognized determinants of
atherosclerosis. In addition to hepatocytes, where both are highly expressed and contribute to plasma
lipoprotein clearance, they are expressed in vascular cells and macrophages. In this study, we examined the effects of human
apoE isoforms and LDLr levels in atherogenic pathways in primary macrophages ex vivo and
atherosclerosis development after bone marrow transfer in vivo using mice expressing human
apoE isoforms and different levels of LDLr expression. Increases in LDLr expression significantly increased
cholesterol delivery into macrophages in culture, and the effects were more prominent with
lipoproteins containing
apoE4 than those containing
apoE3. Conversely, increased LDLr expression reduced
cholesterol efflux in macrophages expressing
apoE4 but not in macrophages expressing
apoE3. Furthermore,
apoE3 protected VLDL from oxidation in vitro more than did
apoE4. In LDLr-deficient mice expressing the human
apoE4 isoform,
Apoe4/4 Ldlr-/-, the replacement of bone marrow cells with those expressing LDLr increased atherosclerotic lesions in a dose-dependent manner compared with mice transplanted with cells having no LDLr. In contrast,
atherosclerosis in
Apoe3/3 Ldlr-/- mice, expressing the human
apoE3 isoform, did not differ by the levels of macrophage LDLr expression. Our results demonstrate that
apoE4, but not
apoE3, in macrophages enhances
atherosclerotic plaque development in mice in an LDLr-dependent manner and suggests that this interaction may contribute to the association of
apoE4 with an increased cardiovascular risk in humans.