ApoE Suppresses Atherosclerosis by Reducing Lipid Accumulation in Circulating Monocytes and the Expression of Inflammatory Molecules on Monocytes and Vascular Endothelium

Abstract

Objective We investigated atheroprotective properties of apoE beyond its ability to lower plasma cholesterol. We hypothesized that apoE reduces atherosclerosis by decreasing lipid accumulation in circulating monocytes and the inflammatory state of monocytes and the vascular endothelium. Methods and Results We developed mice with spontaneous hyperlipidemia with and without plasma apoE: Hypomorphic apoE mice deficient in low-density lipoprotein receptor (Apoeh/hLdlr–/–) were compared to Apoe–/–Ldlr–/– mice. Despite 4-fold more plasma apoE than WT mice, Apoeh/hLdlr–/– mice displayed similar plasma cholesterol as Apoe–/–Ldlr–/– mice but developed 4-fold less atherosclerotic lesions by 5 months of age. The aortic arch of Apoeh/hLdlr–/– mice showed decreased endothelial expression of ICAM-1, PECAM-1, and JAM-A. In addition, Apoeh/hLdlr–/– mice had less circulating leukocytes and pro-inflammatory Ly6Chigh monocytes. These monocytes had decreased neutral lipid content and reduced surface expression of ICAM-1, VLA-4, and L-Selectin. Apoeh/hLdlr–/– mice displayed increased levels of apoA1-rich HDL that were potent in promoting cellular cholesterol efflux. Conclusions Our findings suggest that apoE reduces atherosclerosis in the setting of hyperlipidemia by increasing plasma apoA1-HDL that likely contribute to reduce intracellular lipid accumulation and thereby the activation of circulating leukocytes and the vascular endothelium.

Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

“…Further, aortic lesions were signifi cantly reduced in these mice 3 months after initiating feeding with a Western diet ( 97 ). Protective effects of apoE have been observed in the context of coagulation, macrophage function, oxidative processes, central nervous system physiology, infl ammation, and cell signaling ( 98,99 ). Data suggest that anti-infl ammatory reduce infl ammatory injury in murine models of multiple sclerosis and traumatic brain injury, respectively, and are thought to mediate their effects via binding to LRP (128)(129)(130).…”

“…The synthesis and application of HDL-like nanolipid particles is a recent development in the fi eld of HDL therapy. Earlier, it was shown that, among the 22mer helices of apoA-I, only the N-and C-terminal helices were able to associate with phospholipids while the other regions (either effects of the apolipoprotein are independent of its cholesterol-lowering property (99)(100)(101)(102). Polymorphisms in the apoE gene are associated with enhancement of the infl ammatory response and an increase in mortality in animal models and patients with sepsis ( 103,104 ).…”

“…apoE-containing HDL subspecies were shown to reduce circulating Ly6 hi and increase Ly6 lo monocytes, resulting in decreased monocyte adhesion to the endothelium ( 99 ). Transduction of apoE in macrophages of atherosclerotic apoE Ϫ / Ϫ mice signifi cantly reduces lesion formation without affecting plasma cholesterol levels (107)(108)(109).…”

ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

“…The inducible repair of the hypomorphic phenotype can promote regression and stabilization of atherosclerosis (59,60). The hypoE mice and Apoe / mice were crossed with Ldlr / mice, with the genetic background of the mice being 85% C57BL/6 and 15% 129SvJ (61). Less atherosclerosis was seen in the hypomorphic animals on chow diet.…”

“…The antiproliferative effect is likely due to endogenous apoE bound to the surface of HPSCs interacting with ABCA1 and ABCG1 to promote lipid efflux, resulting in decreased signaling in response to growth factors (80). Monocytosis, particularly of the Ly6C hi subclass, is a risk factor for atherosclerosis (84 (61). This could be a response to an improved cholesterol efflux from the HPSCs in the hypomorphic mice in whom there was a redistribution of some of the plasma apoA-I from VLDL to HDL, making for a more efficient cholesterol efflux acceptor.…”