Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia.
Cholesteryl ester transfer protein (CETP) is a major determinant of plasma levels of high-density lipoprotein-cholesterol (HDL-C) in humans. The anti-atherogenic effect of lowering CETP levels is dependent not only on HDL-C levels but also on a metabolic background of increased low-density lipoprotein or very-low-density lipoprotein. Here we investigated the effects of JTT-705, a chemical inhibitor of CETP, on the development of atherosclerosis in Japanese white rabbits fed on a high cholesterol diet. After 4 weeks on a diet of 0.25% cholesterol-containing chow, 100 mg/kg (low dose) or 300 mg/kg (high dose) JTT-705 was given, and the animals were monitored at weeks 0, 4, 8 and 12. Aortic atherosclerotic lesions were determined at the end of this period. JTT-705 induced a significant increase in HDL-C in the high-dose group [from 21+/-3 to 50+/-7 mg/dl (mean+/-S.E.M.); P <0.0001] compared with the control group (from 21+/-2 to 27+/-2 mg/dl). The atheromatous area was 60+/-9% in the high-dose group and 58+/-9% in the control group. Moreover, correlation analysis showed that triacylglycerol and non-HDL-C levels had a direct relationship with the development of atherosclerosis, but CETP activity and HDL-C levels did not. Thus the CETP inhibitor JTT-705 alone did not have an anti-atherogenic effect in our rabbit model, of severe hypercholesterolaemia suggesting a relatively minor effect of HDL-elevating therapy as compared with decreases in non-HDL-C (or triacylglycerol) levels in patients with severe hypercholesterolaemia, such as familial hypercholesterolaemia.
Huang
Zhiping
Z
Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Takara-machi 13-1, Kanazawa 920-8641, Japan.
Inazu
Akihiro
A
Nohara
Atsushi
A
Higashikata
Toshinori
T
Mabuchi
Hiroshi
H
D000577:Amides; D000818:Animals; D001018:Aortic Diseases / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D001161:Arteriosclerosis / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004036:Diet, Atherogenic; D004952:Esters; D006023:Glycoproteins; D006937:Hypercholesterolemia / Q000150:complications*; D008049:Lipase / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008071:Lipoprotein Lipase / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D011817:Rabbits; D018709:Statistics, Nonparametric; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*
D000577:Amides; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002791:Cholesterol, Dietary; D004952:Esters; D006023:Glycoproteins; D008055:Lipids; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D008049:Lipase; D008071:Lipoprotein Lipase