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Journal of Lipid Research, Vol. 48, 1263-1272, June 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits

Lee A. Morehouse^1,*, Eliot D. Sugarman^*, Patricia-Ann Bourassa^*, Thomas M. Sand^*, Francesca Zimetti, Feng Gao, George H. Rothblat and Anthony J. Milici^**

^* Department of Cardiovascular and Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT
Children's Hospital of Pennsylvania, Philadelphia, PA
Department of Biostatistics, Pfizer Global Research and Development, Groton, CT
^** Department of General Pharmacology, Pfizer Global Research and Development, Groton, CT

Published, JLR Papers in Press, February 26, 2007.

¹ To whom correspondence should be addressed. e-mail: lee.a.morehouse{at}pfizer.com

Cholesteryl ester transfer protein (CETP) inhibitors increase high density lipoprotein-cholesterol (HDL-C) in animals and humans, but whether CETP inhibition will be antiatherogenic is still uncertain. We tested the CETP inhibitor torcetrapib in rabbits fed an atherogenic diet at a dose sufficient to increase HDL-C by at least 3-fold (207 ± 32 vs. 57 ± 6 mg/dl in controls at 16 weeks). CETP activity was inhibited by 70–80% throughout the study. Non-HDL-C increased in both groups, but there was no difference apparent by the study's end. At 16 weeks, aortic atherosclerosis was 60% lower in torcetrapib-treated animals (16.4 ± 3.4% vs. 39.8 ± 5.4% in controls) and aortic cholesterol content was reduced proportionally. Sera from a separate group of rabbits administered torcetrapib effluxed 48% more cholesterol from Fu5AH cells than did sera from control animals, possibly explaining the reduced aortic cholesterol content. Regression analyses indicated that lesion area in the torcetrapib-treated group was strongly correlated with the ratio of total plasma cholesterol to HDL-C but not with changes in other lipid or lipoprotein levels. CETP inhibition with torcetrapib retards atherosclerosis in rabbits, and the reduced lesion area is associated with increased levels of HDL-C.

Supplementary key words cholesteryl ester transfer protein • cholesterol efflux • reverse cholesterol transport

Abbreviations: apoB, apolipoprotein B; AUC, area under the curve; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FC, free cholesterol; FPLC, fast protein liquid chromatography; HDL-C, high density lipoprotein-cholesterol; TPC, total plasma cholesterol

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