Independent protective roles for macrophage Abcg1 and Apoe in the atherosclerotic lesion development

Objective: ATP-binding cassette transporter G1 (Abcg1) and apolipoprotein E (Apoe) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. A possible interaction between Abcg1 and Apoe in cholesterol efflux was postulated, but the potential combined action of these proteins on atherosclerotic lesion formation is unclear. Methods: LDL receptor knockout (KO) mice were transplanted with bone marrow from Abcg1/Apoe double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls and challenged with a high-fat/high-cholesterol diet for 6 weeks to induce atherosclerosis. Results: No differences were found in serum lipid levels. The mean atherosclerotic lesion area in dKO transplanted animals (187 +/- 18 x 10(3) mu m(2)) was 1.4-fold (p < 0.01) increased compared to single knockouts (Abcg1 KO: 138 +/- 5 x 10(3) mu m(2); Apoe KO: 131 +/- 7 x 10(3) mu m(2)) and 1.9-fold (p < 0.001) as compared to WT controls (97 +/- 15 x 10(3) mu m(2)). In vitro cholesterol efflux experiments established that combined deletion of Abcg1 and Apoe leads to a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions: Single deletion of macrophage Abcg1 or Apoe does lead to a moderate non-significant increase in atherosclerotic lesion development as tested by ANOVA, while combined deletion of Abcg1 and Apoe induces a more dramatic and significant increase in atherosclerosis. Our results indicate an additive, independent effect for both macrophage Abcg1 and Apoe in the prevention of atherosclerosis. (C) 2009 Elsevier Ireland Ltd. All rights reserved.