title: Inhibition of hepatic scavenger receptor-class B type I by RNA interference decreases atherosclerosis in rabbits.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Internal Medicine I, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Demetz
authors.forename: Ivan
authors.initials: I
authors.lastname: Tancevski
authors.forename: Kristina
authors.initials: K
authors.lastname: Duwensee
authors.forename: Ursula
authors.initials: U
authors.lastname: Stanzl
authors.forename: Eva
authors.initials: E
authors.lastname: Huber
authors.forename: Christiane
authors.initials: C
authors.lastname: Heim
authors.forename: Florian
authors.initials: F
authors.lastname: Handle
authors.forename: Markus
authors.initials: M
authors.lastname: Theurl
authors.forename: Andrea
authors.initials: A
authors.lastname: Schroll
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.forename: Hermann
authors.initials: H
authors.lastname: Dietrich
authors.forename: Josef R
authors.initials: JR
authors.lastname: Patsch
authors.forename: Philipp
authors.initials: P
authors.lastname: Eller
authors.forename: Andreas
authors.initials: A
authors.lastname: Ritsch
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood; D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000628:therapy*; D015415:Biomarkers / Q000097:blood; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications; D007275:Injections, Intravenous; D008099:Liver / Q000378:metabolism*; D008297:Male; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000378:metabolism*; D011817:Rabbits; D013997:Time Factors; D014162:Transfection
chemical_list: D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D015415:Biomarkers; D018955:CD36 Antigens; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D034741:RNA, Small Interfering