Ben J Wu1, Sudichhya Shrestha2, Kwok L Ong2, Douglas Johns2, Liming Hou2, Philip J Barter2, Kerry-Anne Rye1. 1. 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. 2. 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.).
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. APPROACH AND 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.
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. APPROACH AND 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: Ilona Kareinen; Marc Baumann; Su Duy Nguyen; Katariina Maaninka; Andrey Anisimov; Minoru Tozuka; Matti Jauhiainen; Miriam Lee-Rueckert; Petri T Kovanen Journal: J Lipid Res Date: 2018-03-26 Impact factor: 5.922
Authors: Flavio M Ceci; Mauro Ceccanti; Carla Petrella; Mario Vitali; Marisa P Messina; George N Chaldakov; Antonio Greco; Massimo Ralli; Marco Lucarelli; Antonio Angeloni; Marco Fiore; Giampiero Ferraguti Journal: Curr Neurovasc Res Date: 2021 Impact factor: 1.990