Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits.
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.
Morehouse
Lee A
LA
Department of Cardiovascular and Metabolic and Endocrine Diseases, Pfizer Global Research and Development, Groton, CT. lee.a.morehouse@pfizer.com
Sugarman
Eliot D
ED
Bourassa
Patricia-Ann
PA
Sand
Thomas M
TM
Zimetti
Francesca
F
Gao
Feng
F
Rothblat
George H
GH
Milici
Anthony J
AJ
D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism / Q000517:prevention & control*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D004036:Diet, Atherogenic; D004198:Disease Susceptibility / Q000097:blood / Q000378:metabolism; D008297:Male; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D012044:Regression Analysis
D000924:Anticholesteremic Agents; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D011804:Quinolines; C483909:torcetrapib; D002784:Cholesterol