Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1939-1945
© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Low Levels of Extrahepatic Nonmacrophage ApoE Inhibit Atherosclerosis Without Correcting Hypercholesterolemia in ApoE-Deficient Mice
From the Department of Pharmacological Sciences (F.E.T., D.L.W.), University Medical Center, State University of New York at Stony Brook; the Department of Pathology (Comparative Medicine) (L.L.R.), Wake Forest University School of Medicine, Winston-Salem, NC; and the Poultry Science Department (R.L.W.), Texas A&M University, College Station.
Correspondence to David L. Williams, PhD, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794. E-maildave{at}pharm.sunysb.edu
Abstract—The prevention of atherosclerosis by apolipoprotein E (apoE) is generally attributed to the removal of plasma lipoprotein remnant particles. We developed transgenic apoE-knockout mice expressing apoE specifically in the adrenal gland and found that only 3% of the wild-type plasma level of apoE was sufficient to normalize plasma cholesterol levels in the apoE-deficient mouse. As expected, mice expressing apoE at levels that correct hypercholesterolemia had almost no cholesteryl ester deposition in their aortas. In contrast, their nontransgenic siblings had significant atherosclerosis. Unexpectedly, we found that atherosclerosis was also reduced in 2 transgenic lines expressing too little apoE (<1% to 2% of wild type) to correct their hypercholesterolemia. Gel exclusion chromatographic profiles of plasma lipoproteins and the size distributions of lipoproteins with density <1.063 (low density and very low density lipoproteins), as determined by dynamic laser light scattering, were the same in mice expressing <2 µg/mL plasma apoE and their nontransgenic littermates. We conclude that the antiatherogenic action of low levels of plasma apoE is not due to the clearance of remnant lipoproteins. Thus, low levels of apoE provided systemically, but not made in the liver or in macrophages, can block atherogenesis in the vascular wall independently of normalizing the plasma concentration of atherogenic remnant lipoprotein particles.
Key Words: apoE • atherosclerosis • hypercholesterolemia • transgenic apoE-knockout mice
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