Abstract 284: A Deficiency in the HDL Receptor SR-BI Attenuates Atherosclerotic Plaque Regression in ApoE-Hypomorphic Mice

A deficiency in the HDL receptor, SR-BI, results in accelerated arterial plaque development in ApoE-R61 hypomorphic (“Hypo-E”) mice, however the effect of a lack of SR-BI on atherosclerotic plaque regression is unknown.To explore the role of SR-BI in the regression of arterial atherosclerosis in the Hypo-E mouse model, SR-BI-deficient/Hypo-E (SR-BI-deficient) or SR-BI-expressing/Hypo-E (control) mice were fed high-cholesterol, high-fat diets (HFD) for either 4 or 11weeks (w) to induce the formation of atherosclerotic plaques of similar size in the aortic sinus. The mice were then switched to a normal chow diet (NCD) for 11 w. As had been shown previously by others, atherosclerotic plaques in control mice regressed almost completely during the 11 w of NCD feeding. In contrast, atherosclerotic plaques in SR-BI-deficient mice did not undergo regression but rather continued to grow in size after the switch from HFD to NCD. Concomitantly, circulatory cytokines (IL-6 and TNF-alpha) and atherogenic lipoproteins were elevated by HFD feeding in both groups, and returned to basal levels in control mice, but remained elevated in SR-BI-deficient mice after the switch from HFD to NCD. Immunofluorescence analyses revealed that CD11c-positive dendritic cells were retained in the plaques of SR-BI-deficient Hypo-E mice, which exhibited apparently attenuated expression of CCR7. In a separate experiment SR-BI-deficient mice were fed HFD for 4 weeks and then switched to NCD without or with 0.5% probucol. In untreated group, atherogenic lipoproteins remained elevated and plaques continued to grow after the switch from HFD to NCD, tripling in size by 8 weeks. Probucol treatment resulted in reduced levels of VLDL and LDL cholesterol and halted further lesion growth but did not trigger plaque regression. Probucol treatment was, however, accompanied by a decrease in CD11c staining in atherosclerotic plaques when compared to mice fed HFD for 4 weeks alone or followed by a further 8 weeks of NCD. Probucol also decreased expression of VCAM-1 in coronary arteries. These findings suggest that atherosclerotic plaque regression is impaired in SR-BI deficient mice. Probucol was able to halt further plaque growth but did not trigger plaque regression in SR-BI deficient hypo-E mice.