TY - JOUR
T1 - Macrophage apolipoprotein E reduces atherosclerosis and prevents premature death in apolipoprotein E and scavenger receptor-class BI double-knockout mice
AU - Yu, Hong
AU - Zhang, Wenwu
AU - Yancey, Patricia G.
AU - Koury, Mark J.
AU - Zhang, Youmin
AU - Fazio, Sergio
AU - Linton, MacRae F.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2006/1
Y1 - 2006/1
N2 - Objective - Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. Methods and Results - Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3 to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE-/-SR-BI-/- mice fed 0.5% probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT→DKO mice, and mean serum cholesterol levels were reduced by 70% versus DKO→DKO mice. Lipoprotein profiles and HDL subpopulations in WT→DKO mice were similar to apoE-/+SR-BI-/-→DKO mice and resembled those of SR-BI-/- mice. In WT→DKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKO→DKO mice. Furthermore, the DKO→DKO mice died ≈8 weeks after BMT, whereas WT→DKO mice exhibited a life span >40 weeks after BMT. Conclusions - Macrophage apoE is able to rescue the lethal phenotype of apoE -/-SR-BI-/- mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development.
AB - Objective - Mice null for both apolipoprotein (apo)E and scavenger receptor (SR)-BI (DKO) develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death. The current study examines the ability of macrophage apoE to improve the dyslipidemia, reduce atherosclerosis, and rescue the lethal phenotype of DKO mice. Methods and Results - Initially, bone marrow transplantation (BMT) was unsuccessful, because the DKO mice died from a rapidly fatal anemia 3 to 5 days after lethal irradiation. Therefore, probucol was used to rescue the DKO mice during BMT and was discontinued 2-weeks after BMT, allowing successful reconstitution with donor marrow. Twelve male apoE-/-SR-BI-/- mice fed 0.5% probucol in a chow diet were lethally irradiated and transplanted with either wild-type (WT) or DKO bone marrow. Two-weeks after BMT, apoE was detected in serum in WT→DKO mice, and mean serum cholesterol levels were reduced by 70% versus DKO→DKO mice. Lipoprotein profiles and HDL subpopulations in WT→DKO mice were similar to apoE-/+SR-BI-/-→DKO mice and resembled those of SR-BI-/- mice. In WT→DKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKO→DKO mice. Furthermore, the DKO→DKO mice died ≈8 weeks after BMT, whereas WT→DKO mice exhibited a life span >40 weeks after BMT. Conclusions - Macrophage apoE is able to rescue the lethal phenotype of apoE -/-SR-BI-/- mice by improving the dyslipidemia and dramatically reducing atherosclerotic lesion development.
KW - Apolipoprotein E
KW - Atherosclerosis
KW - Cholesterol
KW - Macrophages
KW - SR-BI
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U2 - 10.1161/01.ATV.0000194096.89476.73
DO - 10.1161/01.ATV.0000194096.89476.73
M3 - Article
C2 - 16269665
AN - SCOPUS:33644832096
SN - 1079-5642
VL - 26
SP - 150
EP - 156
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 1
ER -