Reduced atherosclerotic lesions in mice deficient for total or macrophage-specific expression of scavenger receptor-A.
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.
Babaev
V R
VR
Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300, USA.
Gleaves
L A
LA
Carter
K J
KJ
Suzuki
H
H
Kodama
T
T
Fazio
S
S
Linton
M F
MF
D000818:Animals; D001011:Aorta / Q000473:pathology / Q000648:ultrastructure; D001161:Arteriosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001835:Body Weight; D018955:CD36 Antigens / Q000235:genetics; D017690:Cell Transplantation; D002784:Cholesterol / Q000097:blood; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005260:Female; D005333:Fetus / Q000737:chemistry; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000166:cytology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D018955:CD36 Antigens; D004041:Dietary Fats; D008074:Lipoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051117:Scavenger Receptors, Class A; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D002784:Cholesterol