Blockade of scavenger receptor class B type I raises high density lipoprotein cholesterol levels but exacerbates atherosclerotic lesion formation in apolipoprotein E deficient mice

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 microM 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 < 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 < 0.05), while favourable changes in plasma lipid parameters were achieved. The results of quantitative analysis of atherosclerosis lesion areas were: control, 102691 +/-22871 microm(2) (n = 10); R-138329 0.01%, 119792+/-30842 microm(2) (n = 9); R-138329 0.03%, 141346+/-21934 microm(2) (n = 10); and R-138329 0.10% 203732+/- 36326 microm(2) (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.

High Dietary n-6/n-3 PUFA Ratio Promotes HDL Cholesterol Level, but does not Suppress Atherogenesis in Apolipoprotein E-Null Mice 1

“…A previous study showed that apoE plays scarcely any role in HDL metabolism, and the absence of apoE did not influence the effect of fatty acids on HDL 10) . Several studies using apoE / mice have observed a relationship between HDL metabolism and atherosclerosis recent years [11][12][13] ; therefore, we studied the antiatherogenic effect and HDL-C metabolism by varying the n-6 / n-3 PUFA using apoE / mice. Our results and suggestions may be useful for dietary guidance in human type familial hyperlipoproteinemia or those suffering from hyperlipidemia.…”

Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

“…After submission of this work, Nishizawa and colleagues (80,81) reported the identification of N-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-(2-chloro-5-nitrophenyl)carboxamide (R-138329) as a small molecule that can increase plasma HDLcholesterol in hamsters and mice, decrease murine hepatic selective uptake of [ 3 H]CE from HDL in vivo, exacerbate atherosclerotic lesion formation in apolipoprotein E-deficient mice, and inhibit rodent SR-BI-mediated lipid uptake activity in cultured cells. …”

High-density lipoprotein-based drug discovery for treatment of atherosclerosis

“…It has been reported that 18 weeks of ITX5061-treated mice displayed a 40% reduction of early atherosclerotic lesions in the aortic arch in LDLR -/-mice [103]. However, R-138329, another SR-BI inhibitor, deteriorated atherosclerotic lesion formation in ApoE -/-mice even though it elevated plasma HDL-C [104]. To date, no SR-BI targeted compounds for cardiovascular applications have reached clinical studies.…”