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

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Abstract

Objective: Scavenger 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. Methods: Small 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. Results: After 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. Conclusion: Our 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. © 2012 Elsevier Ireland Ltd.

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Demetz, E., Tancevski, I., Duwensee, K., Stanzl, U., Huber, E., Heim, C., … Ritsch, A. (2012). Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits. Atherosclerosis, 222(2), 360–366. https://doi.org/10.1016/j.atherosclerosis.2012.03.012

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