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.