Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis

Abstract

Genome-wide association studies have linked LRP8 polymorphisms to premature coronary artery disease and myocardial infarction in humans. However, the mechanisms by which dysfunctions of apolipoprotein E receptor-2 (apoER2), the protein encoded by LRP8 gene, influence atherosclerosis have not been elucidated completely. The current study focused on the role of apoER2 in macrophages, a cell type that plays an important role in atherosclerosis. Results showed that apoER2-deficient mouse macrophages accumulated more lipids and were more susceptible to oxidized LDL (oxLDL)-induced death compared to control cells. Consistent with these findings, apoER2 deficient macrophages also displayed defective serum-induced Akt activation and higher levels of the pro-apoptotic protein phosphorylated p53. Furthermore, the expression and activation of peroxisome proliferator-activated receptor γ (PPARγ) was increased in apoER2-deficient macrophages. Deficiency of apoER2 in hypercholesterolemic LDL receptor-null mice (Lrp8−/−Ldlr−/− mice) also resulted in accelerated atherosclerosis with more complex lesions and extensive lesion necrosis compared to Lrp8+/+Ldlr−/− mice. The atherosclerotic plaques of Lrp8−/−Ldlr−/− mice displayed significantly higher levels of p53-positive macrophages, indicating that the apoER2-deficient macrophages contribute to the accelerated atherosclerotic lesion necrosis observed in these animals. Taken together, this study indicates that apoER2 in macrophages limits PPARγ expression and protects against oxLDL-induced cell death. Thus, abnormal apoER2 functions in macrophages may at least in part contribute to the premature coronary artery disease and myocardial infarction in humans with LRP8 polymorphisms. Moreover, the elevated PPARγ expression in apoER2-deficient macrophages suggests that LRP8 polymorphism may be a genetic modifier of cardiovascular risk with PPARγ therapy.

Loss of Reelin protects against atherosclerosis by reducing leukocyte–endothelial cell adhesion and lesion macrophage accumulation

“…There is evidence that the two receptors for Reelin, Apolipoprotein E receptor-2 (Apoer2/Lrp8) and very low-density lipoprotein receptor (Vldlr), influence atherosclerosis severity. In macrophages, Apoer2 reduces stress-induced cell death and potentially retards the development of advanced atherosclerotic plaques (25). In contrast, macrophage Vldlr promotes atherosclerotic lesion development (26).…”

Apolipoprotein E Gene Variants and Risk of Coronary Heart Disease: A Meta-Analysis

“…The determination of blood lipid and lipoprotein levels is one of the coronary risk factors. Apolipoprotein genes involved in lipoprotein synthesis and metabolism play imperative roles in studying the susceptibility to CHD and cerebrovascular disease [6–11]. …”

Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice

“…Indeed, the role of ApoER2 in neuronal survival depends on pathophysiological changes. Notably, ApoER2 is required for protection against neuronal cell loss during normal ageing, but selectively promotes neuronal cell death upon injury ( 19 , 20 ). In addition, ApoE is a major risk factor for several neurodegenerative diseases, and ApoER2 may also be relevant to the pathogenesis of Alzheimer's disease ( 19 ).…”

“…ApoER2 is expressed predominantly in the brain, and its role in neuronal survival depends on the pathological and physiological conditions. ApoER2 is required for protection against neuronal cell loss during normal ageing, while it selectively promotes neuronal cell death upon injury in the adult brain ( 19 , 20 ). Although both PCSK9 and ApoER2 are implicated in brain injury, it remains controversial whether PCSK9 regulates the levels of ApoER2, and whether this has a functional significance in the brain ( 10 ).…”