The key role of apolipoprotein E in atherosclerosis

Abstract

Apolipoprotein E is a multifunctional protein that is synthesized by the liver and several peripheral tissues and cell types, including macrophages. The protein is involved in the efficient hepatic uptake of lipoprotein particles, stimulation of cholesterol efflux from macrophage foam cells in the atherosclerotic lesion, and the regulation of immune and inflammatory responses. Apolipoprotein E deficiency in mice leads to the development of atherosclerosis and re-expression of the protein reduces the extent of the disease. This review presents evidence for the potent anti-atherogenic action of apolipoprotein E and describes our current understanding of its multiple functions and regulation by factors implicated in the pathogenesis of cardiovascular disease.

Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

“…There is greater cardiovascular disease risk associated with the apoE4 allele vs. apoE3, and also with the ApoER2 variant ApoER2-R952Q, and there is evidence that the increased disease predisposition may be related to mechanisms other than changes in lipid status (3)(4)(5)(6)(7)(8)(9). How ApoER2 and its interactive actions with apoE potentially influence the behavior of endothelial cells, which are critically involved in vascular health and disease, has been unknown.…”

“…ApoER2-R952Q also has an additive effect with apoE4, with the combined genotype QQ/E4 showing a 3.9-fold greater susceptibility to cardiovascular disease (5). ApoER2 polymorphism-associated risk is independent of cholesterol levels (3)(4)(5), and although apoE4 may impact LDL abundance (2), there is also evidence that apoE4-associated risk goes well beyond changes in lipoprotein status (6)(7)(8)(9). Whereas there is considerable understanding of the biology of the apoE-ApoER2 tandem in the central nervous system and in Alzheimer's disease (10), the basis for the cardiovascular impact of the receptor and apoE variants remains unclear.…”

Protein Kinase C Controls Vesicular Transport and Secretion of Apolipoprotein E from Primary Human Macrophages

“…ApoE mediates the clearance of triglyceride-rich lipoproteins, inhibits proliferation of smooth muscle cells and lymphocytes, contributes to antigen presentation, and promotes cholesterol efflux from foam cell macrophages (3)(4)(5)(6)(7)(8)(9). ApoE knock-out mice develop hyperlipidemia and severe atherosclerotic lesions (10,11).…”

Structural and Functional Variations in Human Apolipoprotein E3 and E4

“…Human apolipoprotein E (apoE) 2 is a 299-amino acid protein with a molecular mass of 34 kDa. ApoE is encoded by the three alleles (APOE-⑀2, APOE-⑀3, and APOE-⑀4) of a gene on chromosome 19q13.2 determining the three major isoforms, namely apoE2, apoE3, and apoE4 in six phenotypes (1).…”

“…1A). Genetically, the APOE-⑀4 allele is associated with both familial late-onset and sporadic Alzheimer disease (AD) and atherosclerosis (2)(3)(4). AD patients carrying the APOE-⑀4 allele have more profound deposition of ␤-amyloid peptides (A␤) in their brains than those carrying APOE-⑀2 and APOE-⑀3 alleles (5,6).…”