ApoE Attenuates Atherosclerosis via miR-146a

Apolipoprotein E (apoE) has long been recognized as an important regulator of plasma lipoprotein metabolism and cholesterol homeostasis. However, despite decades of research into the biology of apoE, new aspects of its function continue to emerge. In this issue, Li et al1 demonstrate that apoE regulates the expression of an anti-inflammatory microRNA, miR-146a, in monocytes/macrophages. The authors reveal that miR-146a represses nuclear factor-κB (NF-κB) signaling in these cells and that intravascular delivery of miR-146a mimetics can inhibit atherogenesis in mouse models. These findings establish that enhancing miR-146a expression can antagonize atherogenesis and provide an impetus to pursue microRNA-based therapies for vascular inflammatory diseases.Article, see p e1 Initial work that characterized apoE function in the cardiovascular system demonstrated that apoE mediates the uptake of chylomicron remnants and triglyceride-rich very low and intermediate density lipoproteins in the liver. In arteries, together with apoA-I, apoE facilitates cellular cholesterol efflux from macrophage foam cells.2 Genetically engineered deficiency of Apoe in mice results in elevated plasma very low and intermediate density lipoproteins and spontaneous atherogenesis.3,4 Over the past 2 decades, this model has served as the mainstay of atherosclerosis research. Global Apoe deficiency can be rescued by transplantation of wild-type bone marrow, which normalizes plasma cholesterol levels and dramatically reduces atherosclerosis.5,6 Attenuated atherosclerosis is also observed in Apoe -null mice bred with transgenic mice expressing human apoE specifically in macrophages. These mice have plasma cholesterol levels comparable with control littermates.7 Interestingly, a recent study revealed that global hypomorphic expression of apoE has no effect on plasma cholesterol, yet atherosclerosis is suppressed and the expression of monocyte and endothelial cell inflammatory genes are reduced relative to complete Apoe deficiency in the low-density lipoprotein receptor–deficient ( Ldlr −/−) background.8 These studies highlight the importance of apoE in …