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• W2100527417 abstract "Abstract Recent accumulating evidence supports the concept that raising high-density lipoprotein (HDL) may represent an additional therapeutic target for prevention of cardiovascular disease. Scavenger receptor class B type I plays a critical role in plasma HDL cholesterol concentration and structure. This study investigated the effect of scavenger receptor class B type I blockade by a synthetic scavenger receptor class B type I blocker on plasma lipids and atherosclerosis lesion formation in apolipoprotein E (apoE)-deficient mice. N-[4-(4-tert-Butoxycarbonylpiperazin-1-yl)phenyl]-(2-chloro-5-nitrophenyl)carboxamide (R-138329), a novel scavenger receptor class B type I blocker, was identified by screening with a half-maximal inhibitory potency (IC50 value) of around 1 μM in scavenger receptor class B type I-expressing COS-1 cells. Male apoE-deficient mice were fed a chow diet with or without R-138329 (0.01-0.10%, approximately 10–100 mg kg−1, n = 9 or 10) for 12 weeks. Compared with control, treatment with R-138329 at 0.10% caused significant (P &lt; 0.05) increases in plasma HDL cholesterol levels, and decreases in non-HDL cholesterol and triglyceride levels. Furthermore, R-138329 at 0.01% significantly increased the extent of atherosclerotic lesion formation in the aorta by 98% (P &lt; 0.05), while favourable changes in plasma lipid parameters were achieved. The results of quantitative analysis of atherosclerosis lesion areas were: control, 102691 ±22871 μm2 (n = 10); R-138329 0.01%, 119792 ± 30842 μm2 (n = 9); R-138329 0.03%, 141346 ± 21934 μm2 (n = 10); and R-138329 0.10% 203732 ± 36326 μm2 (n = 10). To clarify the mechanistic basis underlying this preferential deterioration, we examined the potential impact on closely related cellular functions. Further studies revealed that the active metabolite of R-138329 inhibited scavenger receptor class B type I-mediated cholesterol efflux. This study demonstrates for the first time pharmacological blockade of scavenger receptor class B type I in apoE-deficient mice. Blockade of scavenger receptor class B type I deteriorates atherosclerotic lesion formation in apoE-deficient mice even though it favourably affects plasma lipid parameters such as raising HDL cholesterol and decreasing non-HDL cholesterol. These results provide new insights for pharmaceutical industry research and development issues." @default.
• W2100527417 created "2016-06-24" @default.
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• W2100527417 date "2006-12-01" @default.
• W2100527417 modified "2023-10-15" @default.
• W2100527417 title "Blockade of scavenger receptor class B type I raises high density lipoprotein cholesterol levels but exacerbates atherosclerotic lesion formation in apolipoprotein E deficient mice" @default.
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• W2100527417 doi "https://doi.org/10.1211/jpp.58.12.0010" @default.
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