1. Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits
- Author
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Demetz, Egon, Tancevski, Ivan, Duwensee, Kristina, Stanzl, Ursula, Huber, Eva, Heim, Christiane, Handle, Florian, Theurl, Markus, Schroll, Andrea, Tailleux, Anne, Dietrich, Hermann, Patsch, Josef R., Eller, Philipp, and Ritsch, Andreas
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SCAVENGER receptors (Biochemistry) , *RNA interference , *ATHEROSCLEROSIS , *HIGH density lipoproteins , *HOMEOSTASIS , *MESSENGER RNA , *LABORATORY rabbits - Abstract
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. [Copyright &y& Elsevier]
- Published
- 2012
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