Branko Simic1, Pavani Mocharla2, Margot Crucet2, Elena Osto2, Adelheid Kratzer2, Simona Stivala2, Susan Kühnast3, Thimoteus Speer4, Petia Doycheva2, Hans M Princen3, Jose W van der Hoorn3, J Wouter Jukema5, Hector Giral2, Anne Tailleux6, Ulf Landmesser2, Bart Staels6, Thomas F Lüscher7. 1. Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland. Electronic address: bsimic@physiol.uzh.ch. 2. Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland. 3. TNO - Metabolic Health Research, Leiden, The Netherlands. 4. Department of Internal Medicine IV, Saarland University Medical Centre, Homburg, Germany. 5. Leiden University Medical Center, Leiden, The Netherlands. 6. Institute Pasteur de Lille, Inserm UMR 1011, University of Lille, France. 7. Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland. Electronic address: cardio@tomluescher.ch.
Abstract
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.
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.CETPmice. METHODS:Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L.CETPmice 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.
Authors: Nicholas J Woudberg; Sarah Pedretti; Sandrine Lecour; Rainer Schulz; Nicolas Vuilleumier; Richard W James; Miguel A Frias Journal: Front Pharmacol Date: 2018-01-22 Impact factor: 5.810