on December 9, 2004
Published online before print December 9, 2004, doi: 10.1161/01.ATV.0000152613.83243.12
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Submitted on September 1, 2004
Accepted on November 19, 2004
Apolipoprotein E Promotes the Regression of Atherosclerosis Independently of Lowering Plasma Cholesterol Levels
Robert L. Raffai *;
From the Cardiovascular Research Institute and Department of Pathology (K.H.W.) and the Division of Vascular Surgery (R.L.F.), University of California, San Francisco, and the San Francisco Veterans Administration Medical Research Center; and the Gladstone Institutes of Cardiovascular Disease and Neurological Disease (R.L.F., S.M.L., K.H.W.), San Francisco, California.
* To whom correspondence should be addressed. E-mail: raffair{at}surgery.ucsf.edu.
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 (Apoeh/h), which express an apoE4-like form of mouse apoE at 
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.
Conclusion--These findings demonstrate for the first time that apolipoprotein E promotes the regression of atherosclerosis independently of lowering plasma cholesterol levels.
Key words: apoE • lipoprotein • atherosclerosis • regression • foam cell
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- Apolipoprotein E and Atherosclerosis: Beyond Lipid Effect
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