Macrophage apolipoprotein E reduces atherosclerosis and prevents premature death in apolipoprotein E and scavenger receptor-class BI double-knockout mice.
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.


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.
Yu
Hong
H
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
Zhang
Wenwu
W
Yancey
Patricia G
PG
Koury
Mark J
MJ
Zhang
Youmin
Y
Fazio
Sergio
S
Linton
MacRae F
MF
D000740:Anemia / Q000401:mortality / Q000517:prevention & control; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D016026:Bone Marrow Transplantation / Q000401:mortality*; D018955:CD36 Antigens / Q000235:genetics*; D002784:Cholesterol / Q000097:blood; D003324:Coronary Artery Disease / Q000401:mortality* / Q000503:physiopathology / Q000628:therapy; D004195:Disease Models, Animal; D006937:Hypercholesterolemia / Q000401:mortality* / Q000503:physiopathology / Q000628:therapy; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D014280:Triglycerides / Q000097:blood; D014916:Whole-Body Irradiation / Q000401:mortality
D001057:Apolipoproteins E; D018955:CD36 Antigens; D014280:Triglycerides; D002784:Cholesterol