Ruud Out1, Menno Hoekstra1, Kim L. L. Habets1, Illiana Meurs1, Vivian de Waard1, Reeni B. Hildebrand1, Yanan Wang1, Giovanna Chimini1, Johan Kuiper1, Theo J.C. van Berkel1, Miranda Van Eck1
1From 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.
Tóm tắt
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±19×10
3
μm
2
after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226±30×10
3
μm
2
;
P
<0.05) and not significantly different from single ABCG1 KO (117±22×10
3
μm
2
) and WT transplanted mice (112±15×10
3
μm
2
).
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.
