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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:150.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage Apolipoprotein E Reduces Atherosclerosis and Prevents Premature Death in Apolipoprotein E and Scavenger Receptor–Class BI Double-Knockout Mice

Hong Yu; Wenwu Zhang; Patricia G. Yancey; Mark J. Koury; Youmin Zhang; Sergio Fazio; MacRae F. Linton

From the Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Departments of Medicine (H.Y., W.Z., P.G.Y., Y.Z., S.F., M.F.L.), Hematology (M.J.K), Pharmacology (M.F.L.), and Pathology (S.F.), Vanderbilt University Medical Center, Nashville, Tenn.

Correspondence to MacRae F. Linton or Sergio Fazio, 383 PRB, 2220 Pierce Ave, Vanderbilt University Medical Center, Nashville, TN 37232-6300. E-mail macrae.linton{at}vanderbilt.edu or sergio.fazio@vanderbilt.edu

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 WTDKO mice, and mean serum cholesterol levels were reduced by 70% versus DKODKO mice. Lipoprotein profiles and HDL subpopulations in WTDKO mice were similar to apoE^+/+SR-BI^–/–DKO mice and resembled those of SR-BI^–/– mice. In WTDKO mice, aortic atherosclerosis was reduced by 88% to 90% versus DKODKO mice. Furthermore, the DKODKO mice died &8 weeks after BMT, whereas WTDKO 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.

Mice null for apolipoprotein E and scavenger receptor class BI develop severe hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarction, and premature death, The current study indicates that macrophage apolipoprotein E is able to rescue the lethal phenotype of apolipoprotein E^–/– scavenger receptor class BI^–/– mice by preventing severe dyslipidemia and atherosclerotic lesion development.

Key Words: macrophages • apolipoprotein E • SR-BI • cholesterol • atherosclerosis

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