This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 26/10/2301    most recent 01.ATV.0000240051.22944.dcv2 01.ATV.0000240051.22944.dcv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Baldán, A. Articles by Edwards, P. A. Search for Related Content PubMed PubMed Citation Articles by Baldán, A. Articles by Edwards, P. A. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Medline Plus Health Information Bone Marrow Transplantation Related Collections Lipid and lipoprotein metabolism Genetically altered mice Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2301.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Impaired Development of Atherosclerosis in Hyperlipidemic Ldlr^–/– and ApoE^–/– Mice Transplanted With Abcg1^–/– Bone Marrow

Ángel Baldán; Liming Pei; Richard Lee; Paul Tarr; Rajendra K. Tangirala; Michael M. Weinstein; Joy Frank; Andrew C. Li; Peter Tontonoz; Peter A. Edwards

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

Related Article:

Is Two out of Three Enough for ABCG1?

Linda K. Curtiss
Arterioscler. Thromb. Vasc. Biol. 2006 26: 2175-2177. [Full Text] [PDF]

This article has been cited by other articles:

				B. L. Burgess, P. F. Parkinson, M. M. Racke, V. Hirsch-Reinshagen, J. Fan, C. Wong, S. Stukas, L. Theroux, J. Y. Chan, J. Donkin, et al. ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo J. Lipid Res., June 1, 2008; 49(6): 1254 - 1267. [Abstract] [Full Text] [PDF]

				J. P. Mauldin, M. H. Nagelin, A. J. Wojcik, S. Srinivasan, M. D. Skaflen, C. R. Ayers, C. A. McNamara, and C. C. Hedrick Reduced Expression of ATP-Binding Cassette Transporter G1 Increases Cholesterol Accumulation in Macrophages of Patients With Type 2 Diabetes Mellitus Circulation, May 27, 2008; 117(21): 2785 - 2792. [Abstract] [Full Text] [PDF]

				A. J. Wojcik, M. D. Skaflen, S. Srinivasan, and C. C. Hedrick A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis J. Immunol., March 15, 2008; 180(6): 4273 - 4282. [Abstract] [Full Text] [PDF]

				R. Out, M. Hoekstra, K. Habets, I. Meurs, V. de Waard, R. B. Hildebrand, Y. Wang, G. Chimini, J. Kuiper, T. J.C. Van Berkel, et al. Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 258 - 264. [Abstract] [Full Text] [PDF]

				X. Zhou, W. He, Z. Huang, A. M. Gotto Jr., D. P. Hajjar, and J. Han Genetic Deletion of Low Density Lipoprotein Receptor Impairs Sterol-induced Mouse Macrophage ABCA1 Expression: A NEW SREBP1-DEPENDENT MECHANISM J. Biol. Chem., January 25, 2008; 283(4): 2129 - 2138. [Abstract] [Full Text] [PDF]

				D. Yan, M. I. Mayranpaa, J. Wong, J. Perttila, M. Lehto, M. Jauhiainen, P. T. Kovanen, C. Ehnholm, A. J. Brown, and V. M. Olkkonen OSBP-related Protein 8 (ORP8) Suppresses ABCA1 Expression and Cholesterol Efflux from Macrophages J. Biol. Chem., January 4, 2008; 283(1): 332 - 340. [Abstract] [Full Text] [PDF]

				A. J. Lusis, J. Yu, and S. S. Wang The Problem of Passenger Genes in Transgenic Mice Arterioscler. Thromb. Vasc. Biol., October 1, 2007; 27(10): 2100 - 2103. [Abstract] [Full Text] [PDF]

				N. Terasaka, N. Wang, L. Yvan-Charvet, and A. R. Tall High-density lipoprotein protects macrophages from oxidized low-density lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1 PNAS, September 18, 2007; 104(38): 15093 - 15098. [Abstract] [Full Text] [PDF]

				D. Yan, M. Jauhiainen, R. B. Hildebrand, K. Willems van Dijk, T. J.C. Van Berkel, C. Ehnholm, M. Van Eck, and V. M. Olkkonen Expression of Human OSBP-Related Protein 1L in Macrophages Enhances Atherosclerotic Lesion Development in LDL Receptor-Deficient Mice Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1618 - 1624. [Abstract] [Full Text] [PDF]

				L. Yvan-Charvet, F. Matsuura, N. Wang, M. J. Bamberger, T. Nguyen, F. Rinninger, X.-C. Jiang, C. L. Shear, and A. R. Tall Inhibition of Cholesteryl Ester Transfer Protein by Torcetrapib Modestly Increases Macrophage Cholesterol Efflux to HDL Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1132 - 1138. [Abstract] [Full Text] [PDF]

				R. Out, M. Hoekstra, I. Meurs, P. de Vos, J. Kuiper, M. Van Eck, and T. J.C. Van Berkel Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 594 - 599. [Abstract] [Full Text] [PDF]

				J. F. Oram and A. M. Vaughan ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease Circ. Res., November 10, 2006; 99(10): 1031 - 1043. [Abstract] [Full Text] [PDF]

				L. K. Curtiss Is Two out of Three Enough for ABCG1? Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2175 - 2177. [Full Text] [PDF]