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

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 26; no. 10; pp. 2301 - 2307
• Main Authors: Baldán, Ángel, Pei, Liming, Lee, Richard, Tarr, Paul, Tangirala, Rajendra K, Weinstein, Michael M, Frank, Joy, Li, Andrew C, Tontonoz, Peter, Edwards, Peter A
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-10-2006; Hagerstown, MD Lippincott
• Subjects: Animals; Apolipoproteins E - deficiency; Apoptosis; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - prevention & control; ATP Binding Cassette Transporter, Sub-Family G, Member 1; ATP-Binding Cassette Transporters - genetics; Biological and medical sciences; Blood and lymphatic vessels; Bone Marrow - metabolism; Bone Marrow Transplantation; Cardiology. Vascular system; Cardiovascular system; Dietary Fats - administration & dosage; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Female; Gene Silencing; Hyperlipidemias - metabolism; Hyperlipidemias - physiopathology; Hyperlipidemias - surgery; Investigative techniques, diagnostic techniques (general aspects); Lipoproteins - deficiency; Lipoproteins - genetics; Macrophages - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Orthopedic surgery; Receptors, LDL - deficiency; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Ultrasonic investigative techniques; Rodentia; LXR; Metabolic diseases; Cardiovascular disease; Lipids; Cholesterol; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; Atherosclerosis; Bone marrow; Hyperlipemia; Dyslipemia; ABCG1; Macrophage
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/01.ATV.0000240051.22944.dc

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.