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

Author:

Kitayama Ken1,Nishizawa Tomohiro1,Abe Koji2,Wakabayashi Kenji3,Oda Tomiichiro4,Inaba Toshimori5,Amemiya Yoshiya5

Affiliation:

1. Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan

2. Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan

3. Lead Discovery Research Laboratories, Sankyo Co., Ltd, Tokyo, Japan

4. Biological Research Laboratories, and R&D Strategy Department, Sankyo Co., Ltd, Tokyo, Japan

5. R&D Strategy Department, Sankyo Co., Ltd, Tokyo, Japan

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 < 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 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.

Publisher

Oxford University Press (OUP)

Subject

Pharmaceutical Science,Pharmacology

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