Effect of macrophage-derived mouse ApoE, human ApoE3-Leiden, and human ApoE2 (Arg158-->Cys) on cholesterol levels and atherosclerosis in ApoE-deficient mice.
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.
Van Eck
M
M
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research , Sylvius Laboratories, Leiden University, The Netherlands. M.Eck@LACDR.LeidenUniv.nl
Herijgers
N
N
Van Dijk
K W
KW
Havekes
L M
LM
Hofker
M H
MH
Groot
P H
PH
Van Berkel
T J
TJ
D000818:Animals; D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood*; D006801:Humans; D008099:Liver / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic
D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; C052720:apolipoprotein E3 (Leidein); D002784:Cholesterol