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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:929.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Macrophage ATP-Binding Cassette Transporter A1 Overexpression Inhibits Atherosclerotic Lesion Progression in Low-Density Lipoprotein Receptor Knockout Mice

Miranda Van Eck; Roshni R. Singaraja; Dan Ye; Reeni B. Hildebrand; Erick R. James; Michael R. Hayden; Theo J.C. Van Berkel

From the Division of Biopharmaceutics (M.V.E., D.Y., R.B.H., T.J.C.V.B.) Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, The Netherlands; Centre for Molecular Medicine and Therapeutics (R.R.S., E.R.J., M.R.H.), Children’s and Women’s Hospital, University of British Columbia, Vancouver, Canada.

Correspondence to M. Van Eck, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333 CC Leiden, The Netherlands. E-mail M.Eck{at}LACDR.LeidenUniv.nl

Background— ATP-binding cassette transporter A1 (ABCA1) is a key regulator of cellular cholesterol and phospholipid transport. Previously, we have shown that inactivation of macrophage ABCA1 induces atherosclerosis in low-density lipoprotein receptor knockout (LDLr–/–) mice. However, the possibly beneficial effects of specific upregulation of macrophage ABCA1 on atherogenesis are still unknown.

Methods and Results— Chimeras that specifically overexpress ABCA1 in macrophages were generated by transplantation of bone marrow from human ABCA1 bacterial artificial chromosome (BAC) transgenic mice into LDLr–/– mice. Peritoneal macrophages isolated from the ABCA1 BAC LDLr–/– chimeras exhibited a 60% (P=0.0006) increase in cholesterol efflux to apolipoprotein AI. To induce atherosclerosis, the mice were fed a Western-type diet containing 0.25% cholesterol and 15% fat for 9, 12, and 15 weeks, allowing analysis of effects on initial lesion development as well as advanced lesions. No significant effect of macrophage ABCA1 overexpression was observed on atherosclerotic lesion size after 9 weeks on the Western-type diet (245±36x10³ µm² in ABCA1 BAC LDLr–/– mice versus 210±20x10³ µm² in controls). However, after 12 weeks, the mean atherosclerotic lesion area in ABCA1 BAC LDLr–/– mice remained only 164±15x10³ µm² (P=0.0008) compared with 513±56x10³ µm² in controls (3.1-fold lower). Also, after 15 weeks on the diet, lesions in mice transplanted with ABCA1 overexpressing bone marrow were still 1.6-fold smaller (393±27x10³ µm² compared with 640±59x10³ µm² in control transplanted mice; P=0.0015).

Conclusion— ABCA1 upregulation in macrophages inhibits the progression of atherosclerotic lesions.

ATP-binding cassette transporter 1 (ABCA1) is a key regulator of cellular cholesterol and phospholipid transport. To investigate the therapeutic benefit of upregulation of macrophage ABCA1, chimeras were created that specifically overexpress ABCA1 in macrophages by bone marrow transplantation. The studies show that ABCA1 upregulation in macrophages inhibited the progression of atherosclerotic lesions.

Key Words: atherosclerosis • leukocytes • cholesterol • transplantation

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