title: Inhibition of cholesteryl ester transfer protein by anacetrapib does not impair the anti-inflammatory properties of high density lipoprotein.
abstract: Cholesteryl ester transfer protein (CETP) is a target of therapeutic intervention for coronary heart disease. Anacetrapib, a potent inhibitor of CETP, has been shown to reduce LDL-cholesterol by 40% and increase HDL-cholesterol by 140% in patients, and is currently being evaluated in a phase III cardiovascular outcomes trial. HDL is known to possess anti-inflammatory properties, however with such large increases in HDL-cholesterol, it is unclear whether CETP inhibition perturbs HDL functionality such as anti-inflammatory effects on endothelial cells. The purpose of the present study was to determine whether CETP inhibition by anacetrapib affects the anti-inflammatory properties of HDL. HDL was isolated from either hamsters treated with vehicle or anacetrapib for 2weeks, or from normal human subjects treated either placebo, 20mg, or 150mg anacetrapib daily for 2weeks. Anacetrapib treatment increased plasma HDL cholesterol levels by 65% and between 48 and 82% in hamsters and humans, respectively. Pre-incubation of human aortic endothelial cells with HDL isolated from both control and anacetrapib treated hamsters suppressed TNFα induced expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin. Similar results were obtained with human HDL samples pre and post treatment with placebo or anacetrapib. Further, HDL inhibited TNFα-induced MCP-1 secretion, monocyte adhesion and NF-κB activation in endothelial cells, and the inhibition was similar between control and anacetrapib treated groups. These studies demonstrate that anacetrapib treatment does not impair the ability of HDL to suppress an inflammatory response in endothelial cells.
authors.affiliation: Department of Atherosclerosis, Merck Research Laboratories, 126 E. Lincoln Ave, Rahway, NJ 07065, USA.
authors.forename: Seongah
authors.initials: S
authors.lastname: Han
authors.forename: Lauretta
authors.initials: L
authors.lastname: Levoci
authors.forename: Paul
authors.initials: P
authors.lastname: Fischer
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Karen
authors.initials: K
authors.lastname: Gagen
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.forename: Timothy
authors.initials: T
authors.lastname: Fisher
authors.forename: Anka G
authors.initials: AG
authors.lastname: Ehrhardt
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Peier
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Johns
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D019040:E-Selectin / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000494:pharmacology*; D023303:Oxazolidinones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D053480:Cholesterol Ester Transfer Proteins; D019040:E-Selectin; D008075:Lipoproteins, HDL; D023303:Oxazolidinones; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C530884:anacetrapib