title: Cholesteryl ester transfer protein inhibition enhances endothelial repair and improves endothelial function in the rabbit.
abstract: OBJECTIVE
  High-density lipoproteins (HDLs) can potentially protect against atherosclerosis by multiple mechanisms, including enhancement of endothelial repair and improvement of endothelial function. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein activity with the anacetrapib analog, des-fluoro-anacetrapib, enhances endothelial repair and improves endothelial function in New Zealand White rabbits with balloon injury of the abdominal aorta.
  
  
  RESULTS
  New Zealand White rabbits received chow or chow supplemented with 0.07% or 0.14% (wt/wt) des-fluoro-anacetrapib for 8 weeks. Endothelial denudation of the abdominal aorta was carried out after 2 weeks. The animals were euthanized 6 weeks postinjury. Treatment with 0.07% and 0.14% des-fluoro-anacetrapib reduced cholesteryl ester transfer protein activity by 81±4.9% and 92±12%, increased plasma apolipoprotein A-I levels by 1.4±0.1-fold and 1.5±0.1-fold, increased plasma HDL-cholesterol levels by 1.8±0.2-fold and 1.9±0.1-fold, reduced intimal hyperplasia by 37±11% and 51±10%, and inhibited vascular cell proliferation by 25±6.1% and 35±6.7%, respectively. Re-endothelialization of the injured aorta increased from 43±6.7% (control) to 69±6.6% and 76±7.7% in the 0.07% and 0.14% des-fluoro-anacetrapib-treated animals, respectively. Aortic ring relaxation and guanosine 3',5'-cyclic monophosphate production in response to acetylcholine were also improved. Incubation of HDLs from the des-fluoro-anacetrapib-treated animals with human coronary artery endothelial cells increased cell proliferation and migration relative to control. These effects were abolished by knockdown of scavenger receptor-B1 and PDZ domain-containing protein 1 and by pharmacological inhibition of phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt.
  
  
  CONCLUSIONS
  Increasing HDL levels by inhibiting cholesteryl ester transfer protein reduces intimal thickening and regenerates functional endothelium in damaged New Zealand White rabbit aortas in an scavenger receptor-B1-dependent and phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt-dependent manner.
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.). k.rye@unsw.edu.au karye@ozemail.com.au ben.wu@unsw.edu.au.
authors: Ben J
authors: BJ
authors: Wu
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.).
authors: Sudichhya
authors: S
authors: Shrestha
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.).
authors: Kwok L
authors: KL
authors: Ong
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.).
authors: Douglas
authors: D
authors: Johns
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.).
authors: Liming
authors: L
authors: Hou
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.).
authors: Philip J
authors: PJ
authors: Barter
authors: From the Centre for Vascular Research, The University of New South Wales, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.); Merck & Co, Inc, Kenilworth, NJ (D.J.); Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia (B.J.W., K.L.O., P.J.B., K.-A.R.); and Lipid Research Group, Heart Research Institute, Sydney, New South Wales, Australia (B.J.W., S.S., K.L.O., L.H., P.J.B., K.-A.R.). k.rye@unsw.edu.au karye@ozemail.com.au ben.wu@unsw.edu.au.
authors: Kerry-Anne
authors: KA
authors: Rye
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001012:Aorta, Abdominal / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016632:Apolipoprotein A-I / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008565:Membrane Proteins; D058426:Neointima; D023303:Oxazolidinones / Q000494:pharmacology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D011817:Rabbits; D012038:Regeneration / Q000187:drug effects*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D057772:Vascular System Injuries / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008565:Membrane Proteins; D023303:Oxazolidinones; C484659:PDZK1 protein, human; D047428:Protein Kinase Inhibitors; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014665:Vasodilator Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); C068961:phosphatidylinositol 4,5-biphosphate kinase; D051057:Proto-Oncogene Proteins c-akt; C530884:anacetrapib
keywords: cholesteryl ester transfer protein; endothelium; inhibition; lipoproteins, HDL