Impaired development of atherosclerosis in hyperlipidemic Ldlr-/- and ApoE-/- mice transplanted with Abcg1-/- bone marrow.
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.


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.
Baldán
Angel
A
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095, USA.
Pei
Liming
L
Lee
Richard
R
Tarr
Paul
P
Tangirala
Rajendra K
RK
Weinstein
Michael M
MM
Frank
Joy
J
Li
Andrew C
AC
Tontonoz
Peter
P
Edwards
Peter A
PA
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000517:prevention & control*; D001853:Bone Marrow / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D020868:Gene Silencing; D006949:Hyperlipidemias / Q000378:metabolism* / Q000503:physiopathology / Q000601:surgery; D008074:Lipoproteins / Q000172:deficiency* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency*
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D004041:Dietary Fats; D008074:Lipoproteins; D011973:Receptors, LDL