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Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2 (Arg158→Cys) on cholesterol levels and atherosclerosis in ApoE- deficient mice

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Author: Eck, M. van · Herijgers, N. · Dijk, K.W. van · Havekes, L.M. · Hofker, M.H. · Groot, P.H.E. · Berkel, T.J.C. van
Type:article
Date:2000
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 1, 20, 119-127
Identifier: 235394
Keywords: Atherosclerosis · Hyperlipidemia · Low density lipoprotein · Animal model · Animal tissue · Cholesterol blood level · Cholesterol transport · Mouse · Nonhuman · Transgenic mouse · Animals · Apolipoprotein E2 · Apolipoprotein E3 · Apolipoproteins E · Arteriosclerosis · Bone Marrow Transplantation · Cholesterol · Humans · Liver · Macrophages, Peritoneal · Mice · Mice, Knockout · Mice, Transgenic

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. Chemicals/CAS: Apolipoprotein E2; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; Cholesterol, 57-88-5