Inhibiting CETP with des-fluoro-anacetrapib nearly doubles re-endothelialization after balloon injury in rabbit aortas (ATVB 2015)

Original title: Cholesteryl ester transfer protein inhibition enhances endothelial repair and improves endothelial function in the rabbit

Arterioscler Thromb Vasc Biol · 29 January 2015 · 6

Wu BJ, Shrestha S, Ong KL, Johns D, Hou L, Barter PJ, Rye KA

New Zealand White rabbits received chow supplemented with 0.07% or 0.14% des-fluoro-anacetrapib for 8 weeks, with endothelial denudation of the abdominal aorta performed after 2 weeks and euthanasia 6 weeks post-injury. The two doses reduced CETP activity by 81 plus or minus 4.9% and 92 plus or minus 12%, raised apoA-I 1.4- and 1.5-fold, and raised HDL cholesterol 1.8- and 1.9-fold, while reducing intimal hyperplasia by 37 plus or minus 11% and 51 plus or minus 10% and vascular cell proliferation by 25 plus or minus 6.1% and 35 plus or minus 6.7%. Re-endothelialization rose from 43 plus or minus 6.7% in controls to 69 plus or minus 6.6% and 76 plus or minus 7.7% at the two doses, alongside improved aortic ring relaxation and cGMP production in response to acetylcholine. HDL from treated animals increased endothelial cell proliferation and migration in vitro, an effect abolished by scavenger receptor-B1 or PDZK1 knockdown or PI3K/Akt inhibition, showing CETP inhibition regenerates functional endothelium through this pathway.

Original 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.

Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.