Reduced Atherosclerotic Lesions in Mice Deficient for Total or Macrophage-Specific Expression of Scavenger Receptor-A

Abstract

Abstract —The absence of the scavenger receptor A (SR-A)-I/II has produced variable effects on atherosclerosis in different murine models. Therefore, we examined whether SR-AI/II deficiency affected atherogenesis in C57BL/6 mice, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, and whether the deletion of macrophage SR-AI/II expression would modulate lesion growth in C57BL/6 mice and LDL receptor (LDLR) −/− mice. SR-AI/II–deficient (SR-AI/II −/− ) female and male mice on the C57BL/6 background were challenged with a butterfat diet for 30 weeks. No differences were detected in plasma lipids between SR-AI/II −/− and SR-AI/II +/+ mice, whereas both female and male SR-AI/II −/− mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II +/+ mice. Next, to analyze the effect of macrophage-specific SR-AI/II deficiency in atherogenesis, female C57BL/6 mice were lethally irradiated, transplanted with SR-AI/II −/− or SR-AI/II +/+ fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR −/− mice were reconstituted with SR-AI/II −/− or SR-AI/II +/+ fetal liver cells and challenged with a Western diet for 10 weeks. No significant differences in plasma lipids and lipoprotein profiles were noted between the control and experimental groups in either experiment. SR-AI/II −/− →C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II +/+ →C57BL/6 mice. A similar level of reduction (60%) in lesion area was noted in the proximal aorta and the entire aorta en face of SR-AI/II −/− →LDLR −/− mice compared with SR-AI/II +/+ →LDLR −/− mice. These results demonstrate in vivo that SR-AI/II expression has no impact on plasma lipid levels and that macrophage SR-AI/II contributes significantly to atherosclerotic lesion formation.