Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2 (Arg158→Cys) on cholesterol levels and atherosclerosis in ApoE- deficient mice
article
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
Topics
AtherosclerosisHyperlipidemiaLow density lipoproteinAnimal modelAnimal tissueCholesterol blood levelCholesterol transportMouseNonhumanTransgenic mouseAnimalsApolipoprotein E2Apolipoprotein E3Apolipoproteins EArteriosclerosisBone Marrow TransplantationCholesterolHumansLiverMacrophages, PeritonealMiceMice, KnockoutMice, Transgenic
TNO Identifier
235394
ISSN
10795642
Source
Arteriosclerosis, Thrombosis, and Vascular Biology, 20(1), pp. 119-127.
Pages
119-127
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