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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:258.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels

Ruud Out; Menno Hoekstra; Kim Habets; Illiana Meurs; Vivian de Waard; Reeni B. Hildebrand; Yanan Wang; Giovanna Chimini; Johan Kuiper; Theo J.C. Van Berkel; Miranda Van Eck

From the Division of Biopharmaceutics (R.O., M.H., K.H., I.M., V.d.W., R.B.H., Y.W., J.K., T.J.C.V.B., and M.V.E.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, The Netherlands; and the Centre d’Immunologie de Marseille Luminy (G.C.), Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université de la Méditerranée, Marseille, France.

Correspondence to R. Out, Division of Biopharmaceutics, Gorlaeus Laboratories, Einsteinweg 55, 2333CC Leiden, The Netherlands. E-mail r.out{at}lacdr.leidenuniv.nl

Abstract

Objective— The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis.

Methods and Results— LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156±19x10³ µm² after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226±30x10³ µm²; P<0.05) and not significantly different from single ABCG1 KO (117±22x10³ µm²) and WT transplanted mice (112±15x10³ µm²).

Conclusions— Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts.

To assess the combined role of macrophage ABCA1 and ABCG1 in atherosclerosis, we generated LDL receptor knockout mice that are selectively deficient in ABCA1 and ABCG1 by using bone marrow transfer. Despite relatively low plasma cholesterol levels these mice show distinct atherosclerosis and massive accumulation of lipids in tissue macrophages.

Key Words: ABCA1 • ABCG1 • atherosclerosis • macrophage • transplantation • cholesterol

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