Abstract

OBJECTIVE:

The mechanisms by which apolipoprotein E (apoE) can promote the regression of atherosclerosis are not well understood. This study examined whether apoE can promote atherosclerosis regression independently of lowering plasma cholesterol levels.

METHODS AND RESULTS:

We studied hypomorphic apoE mice (Apoe(h/h)), which express an apoE4-like form of mouse apoE at approximately 2% to 5% of normal levels in plasma and are normolipidemic. After 18 weeks of diet-induced hypercholesterolemia, which resulted in advanced aortic atherosclerotic lesions composed of a lipid-rich layer of foam cells covering a fibrotic core, 2 groups of mice were fed a chow diet for 16 weeks. One group continued to express low levels of apoE; the other was induced to express physiological levels of plasma apoE by Cre-mediated recombination of the hypomorphic Apoe allele. In both groups, plasma cholesterol levels fell rapidly to similar levels, and histological analysis at 16 weeks revealed elimination of the foam-cell layer. However, physiological levels of plasma apoE also enhanced the removal of neutral lipids from the fibrotic cores.

CONCLUSIONS:

These findings demonstrate for the first time that apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels. Using Apoeh/hMx1-Cre mice we have begun to address apolipoprotein E-mediated mechanisms of atherosclerosis regression. We report the existence of a cholesterol-independent role of apolipoprotein E in atherosclerosis regression. This mechanism is critical for lipid removal from the fibrotic component of the plaque but not from the foam cell-rich layer beneath the endothelium.