Anacetrapib, but not evacetrapib, impairs endothelial function in CETP-transgenic mice in spite of marked HDL-C increase.
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.



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.



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.



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.
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland. Electronic address: bsimic@physiol.uzh.ch.
Branko
B
Simic
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Pavani
P
Mocharla
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Margot
M
Crucet
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Elena
E
Osto
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Adelheid
A
Kratzer
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Simona
S
Stivala
TNO - Metabolic Health Research, Leiden, The Netherlands.
Susan
S
Kühnast
Department of Internal Medicine IV, Saarland University Medical Centre, Homburg, Germany.
Thimoteus
T
Speer
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Petia
P
Doycheva
TNO - Metabolic Health Research, Leiden, The Netherlands.
Hans M
HM
Princen
TNO - Metabolic Health Research, Leiden, The Netherlands.
Jose W
JW
van der Hoorn
Leiden University Medical Center, Leiden, The Netherlands.
J Wouter
JW
Jukema
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Hector
H
Giral
Institute Pasteur de Lille, Inserm UMR 1011, University of Lille, France.
Anne
A
Tailleux
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland.
Ulf
U
Landmesser
Institute Pasteur de Lille, Inserm UMR 1011, University of Lille, France.
Bart
B
Staels
Center for Molecular Cardiology, Campus Schlieren, University of Zürich, Switzerland; University Heart Center, Cardiology, University Hospital Zürich, Switzerland. Electronic address: cardio@tomluescher.ch.
Thomas F
TF
Lüscher
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000633:toxicity; D053318:Apolipoprotein E3 / Q000235:genetics; D043303:Aryldialkylphosphatase / Q000097:blood; D001569:Benzodiazepines / Q000494:pharmacology* / Q000633:toxicity; D015415:Biomarkers / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008822:Mice, Transgenic; D023303:Oxazolidinones / Q000494:pharmacology* / Q000633:toxicity; D010641:Phenotype; D017382:Reactive Oxygen Species / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation; D014664:Vasodilation / Q000187:drug effects*
D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D023303:Oxazolidinones; D017382:Reactive Oxygen Species; D014280:Triglycerides; D001569:Benzodiazepines; C568301:evacetrapib; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse; C530884:anacetrapib
CETP; Endothelial dysfunction; HDL-Cholesterol; Hyperlipidemia