Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Peripheral Vascular Disease, Cardiovascular System & Cardiology, Gene therapy, Hypercholesterolemia, Cholesteryl ester transfer protein, HDL receptor, Rabbits, CHOLESTERYL ESTER TRANSFER, E-DEFICIENT MICE, TRANSFER PROTEIN EXPRESSION, CORONARY-ARTERY-DISEASE, SR-BI, HDL RECEPTOR, IMMUNONEPHELOMETRIC ASSAYS, LESION DEVELOPMENT, GENE-TRANSFER, LIPOPROTEIN, Animals, Apolipoprotein A-I, Apolipoproteins B, Atherosclerosis, Biomarkers, CD36 Antigens, Cell Line, Tumor, Cholesterol Ester Transfer Proteins, Cholesterol Esters, Cholesterol, HDL, Cholesterol, VLDL, Disease Models, Animal, Genetic Therapy, Humans, Injections, Intravenous, Liver, Male, RNA Interference, RNA, Small Interfering, Time Factors, Transfection, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences

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.