Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia.

Abstract

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.

• Authors: Zhiping Huang, Akihiro Inazu, Atsushi Nohara, Toshinori Higashikata, Hiroshi Mabuchi
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 103 Issue 6 Pg. 587-94 (Dec 2002) ISSN: 0143-5221 [Print] England
• PMID: 12444911 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Carrier Proteins
• Cholesterol Ester Transfer Proteins
• Cholesterol, Dietary
• Esters
• Glycoproteins
• Lipids
• Sulfhydryl Compounds
• dalcetrapib
• Lipase
• Lipoprotein Lipase

Topics

• Amides
• Animals
• Aortic Diseases (blood, pathology, prevention & control)
• Arteriosclerosis (blood, pathology, prevention & control)
• Body Weight
• Carrier Proteins (antagonists & inhibitors)
• Cholesterol Ester Transfer Proteins
• Cholesterol, Dietary (administration & dosage)
• Diet, Atherogenic
• Esters
• Glycoproteins
• Hypercholesterolemia (complications)
• Lipase (metabolism)
• Lipids (blood)
• Lipoprotein Lipase (blood)
• Liver (enzymology)
• Male
• Rabbits
• Statistics, Nonparametric
• Sulfhydryl Compounds (therapeutic use)