Abstract 1448: Enhanced Foam Cell Formation, Inflammation, and Atherosclerosis in LDL Receptor knockout Mice with a Combined Deletion of Macrophage SR-BI and ABCA1.
ABCA1 mediates the efflux of cholesterol from macrophage foam cells to lipid-poor apoAI, while SR-BI promotes efflux to mature HDL. To get further insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis, LDL receptor knockout (LDLr KO) mice were transplanted with bone marrow from ABCA1xSR-BI double KO mice. Serum cholesterol levels were only 863±118 mg/dL in ABCA1xSR-BI double KO transplanted animals on Western-type diet, as compared to 1390±98 mg/dL (p<0.01) for single ABCA1 KO, 1600±13 mg/dL (p<0.001) for single SR-BI KO, and 1610±75 mg/dL (p<0.001) for control transplanted animals. Despite the lower serum cholesterol levels, LDLr KO mice reconstituted with ABCA1xSR-BI double KO bone marrow showed more extreme foam cell formation in spleens and in macrophages isolated from the peritoneal cavity (22±1.2% (p<0.001) as compared to only 7.5±1.1% for single ABCA1 KO and 0.2±0.04% for single SR-BI KO and 2.5±0.5% for control transplanted animals). Interestingly, ABCA1xSR-BI double KO transplanted animals also showed a dramatic enhancement of systemic inflammation. Furthermore, after 9 weeks Western-type diet feeding atherosclerotic lesion development was more extensive in the LDLr KO mice reconstituted with ABCA1xSR-BI double KO bone marrow (724±51x103 μm2) as compared to single ABCA1 KO (469±53x103 μm2, p<0.001), SR-BI KO (529±30x103 μm2, p<0.01), and wildtype (307±32x103 μm2, p<0.001) reconstituted animals (see figure⇓). In conclusion, combined deletion of macrophage SR-BI and ABCA1 identifies the essential function of both ABCA1 and SR-BI in cholesterol efflux from macrophages and atherosclerotic lesion development.