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) Ϫ/Ϫ mice. SR-AI/II-deficient (SR-AI/IIϪ/Ϫ ) 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 Ϫ/Ϫ and SR-AI/II ϩ/ϩ mice, whereas both female and male SR-AI/II Ϫ/Ϫ mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ 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 Ϫ/Ϫ or SR-AI/II ϩ/ϩ fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR Ϫ/Ϫ mice were reconstituted with SR-AI/II Ϫ/Ϫ or SR-AI/II ϩ/ϩ 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 Ϫ/Ϫ 3 C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II ϩ/ϩ 3 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 4,5 that are generated through alternative splicing of a single gene. 6 The uptake of modified-LDL cholesterol by SR-AI/II has been proposed to play a key role in the pathogenesis of atherosclerosis by promoting lipid accumulation and foam cell formation by the macrophage. 7 The SR-AI/II is expressed predominantly by macrophages 8,9 and is widely expressed by macrophages and foam cells of atherosclerotic lesions. 10 -12 However, smooth muscle cells and endothelial cells may also express the SR-AI/II, 13,14 particularly in the presence of oxidative stress and certain growth factors in vitro 15 and in vivo. 16 The relative contributions of SR-AI/II expression by macrophages, endothelial cells, and smooth muscle cells to atherosclerotic lesion formation in vivo remain uncertain. See page 2506The development of mice with targeted disruption of the SR-AI/II gene provided an important model in which to examine the role of the SR-AI/II in atherosclerosis in vivo, 17 yet the results of these studies have been conflicting. [17][18][19] The absence of SR-AI/II in apoE-deficient (apoE Ϫ/Ϫ ) mice induced a 58% reduction in lesion size compared with control apoE Ϫ/Ϫ mice. 17 In contrast, mice deficient for both the SR-AI/II (SR-AI/II Ϫ/Ϫ ) and the LDL receptor (LDLR Ϫ/Ϫ ) had 28% and 23% reductions in aortic lesion area after 4 and 12 weeks, respectively, of a high-fat diet containing 1.25%...

Glycoxidised LDL isolated from subjects with impaired glucose tolerance increases CD36 and peroxisome proliferator–activator receptor γ gene expression in macrophages

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Scavenger receptor class A type I/II (CD204) null mice fail to develop fibrosis following silica exposure

“…DNA samples were extracted from mouse tail and amplified using forward (5Ј-CAAGTGATA-CATCTCAAGGTC-3Ј), reverse (5Ј-CTGTAGATTCACGGACTC-TG-3Ј), and Neo insert (5Ј-GAGGAGTAGAAGGTGGCGCGAA-3Ј) primers (Operon Technologies, Alameda, CA) encompassing the site of the SR A I/II and Neo insert (5). Amplification was performed in a PTC-200 Gradient Cycler (MJ Research, Las Vegas, NV) with the following parameters: 1 min 94°C, 1 min 60°C, 1 min 72°C and subjected to 35 cycles of PCR.…”

TR4 nuclear receptor functions as a fatty acid sensor to modulate CD36 expression and foam cell formation

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