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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:119.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effect of Macrophage-Derived Mouse ApoE, Human ApoE3-Leiden, and Human ApoE2 (Arg158Cys) on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice

Miranda Van Eck; Nicole Herijgers; Ko Willems Van Dijk; Louis M. Havekes; Marten H. Hofker; Pieter H. E. Groot; Theo J. C. Van Berkel

From the Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research (M.V.E., N.H., T.J.C.V.B.), the Department of Human Genetics (K.W.V.D., M.H.H.), Sylvius Laboratories, Leiden University, and TNO Prevention and Health (L.M.H.), Leiden, The Netherlands; and SmithKline Beecham Pharmaceuticals (P.H.E.G.), NFSP(N), Coldharbour Road, Harlow, Essex CM19 5AD, UK.

Correspondence to M. Van Eck, MSc, Division of Biopharmaceutics, Sylvius Laboratories, Leiden University, PO Box 9503, 2300 RA Leiden, The Netherlands. E-mail M.Eck{at}LACDR.LeidenUniv.nl

Abstract—The effect of monocyte/macrophage-derived wild-type mouse apolipoprotein E (apoE), human apoE3-Leiden, and human apoE2 on serum cholesterol levels and the development of atherosclerosis in apoE-deficient (apoe–/–) mice was investigated by using bone marrow transplantation (BMT). At 4 weeks after BMT, murine apoe+/+ bone marrow reduced serum cholesterol levels by 87% in apoe–/– mice, whereas macrophage-derived human apoE3-Leiden and human apoE2 induced a maximal, transient reduction of 35% and 48%, respectively. At 4 months after BMT, atherosclerosis was 23-fold (P<0.001) reduced in apoe+/+apoe–/– mice, whereas no significant reduction in apoE3-Leiden.apoe–/–apoe–/– and apoE2.apoe–/–apoe–/– mice could be demonstrated. A highly significant decrease in serum cholesterol levels (78% reduction) and atherosclerosis (21-fold, P<0.001) was found in apoE3-Leiden.apoe–/– animals expressing high levels of apoE in multiple tissues, whereas apoE2 was ineffective even at high concentrations. Furthermore, in contrast to apoE-deficient macrophages, cholesterol efflux from apoE2 or apoE3-Leiden macrophages was not impaired. In conclusion, apoE3-Leiden as well as apoE2 are less effective in reducing cholesterol levels and atherosclerosis in apoe–/– animals, compared with apoe+/+, with apoE2<apoE3-Leiden<apoe+/+, irrespective of the observed adequate efflux of cholesterol from macrophages expressing apoE2 and apoE3-Leiden, indicating that normalization of cholesterol efflux by macrophages is not accompanied by measurable effects on lesion growth.

Key Words: apolipoprotein E • atherosclerosis • hyperlipidemia • macrophages • bone marrow transplantation

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