Apolipoprotein E Suppresses Atherosclerosis by Reducing Leukocyte Recruitment to Atheroma

We investigated the anti‐atherosclerotic properties of apoE beyond its ability to lower plasma cholesterol level. We hypothesized that in the setting of dyslipidemia, apoE reduces the recruitment of leukocytes to atheroma. Mice developing spontaneous dyslipidemia in the presence and absence of apoE expression were studied: Hypomorphic apoE mice deficient in low‐density lipoprotein receptor ( Apoe h/h Ldlr −/− ) were compared to mice deficient in apoE and Ldlr ( Apoe −/− Ldlr −/− ). Despite similar plasma cholesterol levels (597.5±24.3 mg/dl versus 662.4±26.4 mg/dl, respectively), Apoe h/h Ldlr −/− mice developed ~4 fold less oil red O and ~3 fold less macrophage‐positive aortic surface area than Apoe −/− Ldlr −/− mice by five months of age. To examine the role of apoE on leukocyte recruitment, we performed adoptive transfer of fluorescently‐labeled leukocytes in both mouse models. Cross‐sections of the aortic root and isolated enface aortic arch were examined by confocal microscopy. Shoulder regions of aortic lesions accumulated two fold more fluorescent‐leukocytes in Apoe −/− Ldlr −/− than in Apoe h/h Ldlr −/− mice. Moreover, the endothelium of Apoe −/− Ldlr −/− mice displayed elevated levels of PECAM and JAM‐A. Taken together these results indicate that apoE reduces atherosclerosis by suppressing the expression of cell‐adhesion molecules on the endothelium and in turn the recruitment of leukocytes to atheroma.