What do we know about apolipoprotein E and the prevention of cardiovascular disease?

Abstract

Apolipoprotein E (ApoE) serves as a ligand for low-density lipoprotein (LDL) receptor and LDL receptor-related protein and plays an important role in the clearance of triglyceride-rich lipoproteins. The links between ApoE and cardiovascular disease has been shown in animal models and numerous epidemiological studies. Deletion of the APOE gene in mice resulted in high plasma cholesterol and spontaneous atherosclerosis. Atheroma formation in APOE-deficient mice can be prevented by expression of ApoE through various genetic transfer techniques. These effects may be independent of the effect on cholesterol levels, suggesting a direct antiatherogenic effect of ApoE. In humans, the APOE genotypes are important determinants of LDL-C and were highest in subjects with the ε4 allele, intermediate in ε3 subjects, and lowest in ε2 subjects. Targeting APOE expression or ApoE levels represents an attractive means of reversing or preventing atherosclerosis. Infusion of recombinant adenovirus containing ApoE, intramuscular injection of plasmid vector encoding for APOE3 cDNA, or infusion of recombinant ApoE in animal models have all resulted in reduction in cholesterol and prevention of atherosclerosis. The use of peptide models of ApoE in animals has also shown some potential in reducing atherosclerosis. However, the short half-lives of recombinant ApoE or its peptide models are a limitation to their usefulness. New modalities for drug delivery that allow sustained delivery of ApoE, such as the multivesicular liposome depot-delivery system (DepoFoam) may pave the way for the use of ApoE as a means of therapy in atherosclerosis prevention. Interactions between APOE genotypes and response to lipid-lowering therapy is another area of focus when considering the role of ApoE in the prevention of atherosclerosis. © 2004 Wiley-Liss, Inc.