Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase
| Autor: | J. Wouter Jukema, Petia Doycheva, Anne Tailleux, Susan Kühnast, Ulf Landmesser, Pavani Mocharla, Hans M.G. Princen, Elena Osto, José W.A. van der Hoorn, Bart Staels, Adelheid Kratzer, Branko Simic, Thomas F. Lüscher, Simona Stivala, Margot Crucet, Thimoteus Speer, Hector Giral |
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| Přispěvatelé: | University of Zurich, Lüscher, Thomas F |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Apolipoprotein E3 Biomedical Innovation 030204 cardiovascular system & hematology Benzodiazepines chemistry.chemical_compound 0302 clinical medicine Life Anacetrapib Hyperlipidemia Endothelial dysfunction chemistry.chemical_classification Anticholesteremic Agents Up-Regulation Vasodilation Phenotype 10209 Clinic for Cardiology Female lipids (amino acids peptides and proteins) Efflux MHR - Metabolic Health Research Cardiology and Cardiovascular Medicine Healthy Living Genetically modified mouse medicine.medical_specialty Mice Transgenic 610 Medicine & health Biology Diet High-Fat 2705 Cardiology and Cardiovascular Medicine 03 medical and health sciences Internal medicine CETP medicine Animals Humans Genetic Predisposition to Disease Oxazolidinones Triglycerides Dyslipidemias Reactive oxygen species Aryldialkylphosphatase Cholesterol Cholesterol HDL medicine.disease Cholesterol Ester Transfer Proteins Disease Models Animal 030104 developmental biology Endocrinology chemistry HDL-Cholesterol Endothelium Vascular ELSS - Earth Life and Social Sciences Reactive Oxygen Species Biomarkers Evacetrapib |
| Zdroj: | Atherosclerosis, 257, 186-194 Atherosclerosis Atherosclerosis, 257, 184-194 |
| Popis: | Background and aims. High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice. Methods. Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETP mice on high cholesterol diet and treated with anacetrapib (3 mg/kg/day), evacetrapib (3 mg/kg/day) or placebo. Cholesterol efflux was assessed ex-vivo in mice treated with CETP inhibitors for 3 weeks on a normal chow diet. Endothelial function was analyzed at week 21 in isolated aortic rings, and serum lipoproteins assessed by fast-performance liquid chromatography. Results. Anacetrapib and evacetrapib increased HDL-C levels (5- and 3.4-fold, resp.) and reduced triglycerides (−39% vs. placebo, p = 0.0174). Total cholesterol levels were reduced only in anacetrapib-treated mice (−32%, p = 0.0386). Cholesterol efflux and PON-1 activity (+45% and +35% vs. control, p < 0.005, resp.) were increased, while aortic ROS production was reduced with evacetrapib (−49% vs. control, p = 0.020). Anacetrapib, but not evacetrapib, impaired endothelium dependent vasorelaxation (p < 0.05). In contrast, no such effects were observed in E3L mice for all parameters tested. Conclusions. Notwithstanding a marked rise in HDL-C, evacetrapib did not improve endothelial function, while anacetrapib impaired it, suggesting that CETP inhibition does not provide vascular protection. Anacetrapib exerts unfavorable endothelial effects beyond CETP inhibition, which may explain the neutral results of large clinical trials in spite of increased HDL-C. |
| Databáze: | OpenAIRE |
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