Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits

ObjectiveScavenger receptor-class B type I (SR-BI), the receptor for HDL-cholesterol, plays a key role in HDL metabolism, whole body cholesterol homeostasis, and reverse cholesterol transport. We investigated the in vivo impact of hepatic SR-BI inhibition on lipoprotein metabolism and the development of atherosclerosis employing RNA interference.MethodsSmall hairpin RNA plasmid specific for rabbit SR-BI was complexed with galactosylated poly-l-lysine, allowing an organ-selective, receptor-mediated gene transfer. Rabbits were fed a cholesterol-rich diet, and were injected with plasmid-complexes once a week.ResultsAfter 2 weeks of treatment hepatic SR-BI mRNA levels were reduced by 80% accompanied by reduced SR-BI protein levels and a modulation of the lipoprotein profile. Rabbits treated with SR-BI-specific plasmid-complexes displayed higher cholesteryl ester transfer from HDL to apoB-containing lipoproteins, lower HDL-cholesterol, and higher VLDL-cholesterol levels, when compared to controls. In a long-term study, this gene therapeutic intervention led to a similar modulation of the lipoprotein profile, to lower total cholesterol levels, and most importantly to a 50% reduction of the relative atherosclerotic lesion area.ConclusionOur results are another indication that the role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits - a CETP-expressing animal model displaying a manlike lipoprotein profile may be different from the one found in rodents.

► Small hairpin RNA specific for SR-BI nucleotides 214-232 reduces SR-BI expression in vitro. ► SiRNA treatment reduces liver expression of SR-BI in New Zealand White rabbits. ► Liver specific inhibition of SR-BI leads to a 50% reduction of atherosclerosis in cholesterol fed rabbits. ► The role of SR-BI in rabbits may be different from the one found in rodents.