Published online before print August 3, 2006, doi: 10.1161/01.ATV.0000240051.22944.dc
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr–/– and ApoE–/– Mice Transplanted With Abcg1–/– Bone Marrow
From the Departments of Biological Chemistry (Á.B., R.L., P. Tarr, M.M.W., P.A.E.), Medicine (Á.B., R.L., P. Tontonoz, R.K.T., J.F., P.A.E.), Pathology and Laboratory Medicine (L.P., P.T.), the Howard Hughes Medical Institute (P. Tontonoz) and the Molecular Biology Institute (P.A.E., P. Tontonoz), UCLA, Los Angeles, Calif; Department of Cellular and Molecular Medicine (A.C.L.), UCSD, La Jolla, Calif.
Correspondence to Peter A. Edwards, Department of Biological Chemistry, CHS 33-257, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095. E-mail pedwards{at}mednet.ucla.edu
Objective— The lungs of Abcg1–/– mice accumulate macrophage foam cells that contain high levels of unesterified and esterified cholesterol, consistent with a role for ABCG1 in facilitating the efflux of cholesterol from macrophages to high-density lipoprotein (HDL) and other exogenous sterol acceptors. Based on these observations, we investigated whether loss of ABCG1 affects foam cell deposition in the artery wall and the development of atherosclerosis.
Methods and Results— Bone marrow from wild-type or Abcg1–/– mice was transplanted into Ldlr–/– or ApoE–/– mice. After administration of a high-fat/high-cholesterol diet, plasma and tissue lipid levels and atherosclerotic lesion size were quantified and compared. Surprisingly, transplantation of Abcg1–/– bone marrow cells resulted in a significant reduction in lesion size in both mouse models, despite the fact that lipid levels increased in the lung, spleen, and kidney. Lesions of Ldlr–/– mice transplanted with Abcg1–/– cells contained increased numbers of apoptotic cells. Consistent with this observation, in vitro studies demonstrated that Abcg1–/– macrophages were more susceptible to oxidized low-density lipoprotein (ox-LDL)-dependent apoptosis than Abcg1+/+ cells.
Conclusions— Diet-induced atherosclerosis is impaired when atherosclerotic-susceptible mice are transplanted with Abcg1–/– bone marrow. The demonstration that Abcg1–/– macrophages undergo accelerated apoptosis provides a mechanism to explain the decrease in the atherosclerotic lesions.
Transplantation of Abcg1–/– bone marrow into Ldlr–/– or ApoE–/– mice reduced atherosclerosis. The lesions of Ldlr–/– mice transplanted with Abcg1–/– cells also contained increased numbers of apoptotic cells. Further, Abcg1–/– macrophages are more susceptible to ox-LDL–induced apoptosis. These data suggest that loss of ABCG1 results in apoptosis and decreased atherosclerosis.
Key Words: ABCG1 • atherosclerosis • cholesterol • LXR • macrophage
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Arterioscler Thromb Vasc Biol 2006 26: 2175-2177.
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