Abstract 10735: Effects of Cholesteryl Ester Transfer Protein Inhibition on Endothelial Repair and Function
Objectives: HDL protect against atherosclerosis by multiple mechanisms, such as removing cholesterol from the artery wall. HDL also inhibit vascular inflammation and oxidation, enhance endothelial repair and improve endothelial function. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from HDL to other lipoprotein fractions. Inhibition of CETP activity is an effective therapeutic strategy for increasing HDL levels. This study asks if inhibition of CETP activity in New Zealand White (NZW) rabbits with des-fluoro-anacetrapib improves endothelial repair and enhances endothelial function.
Methods: NZW rabbits (n=6/group) received normal 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 with a balloon catheter after 2 weeks. The animals were sacrificed 6 weeks post-balloon injury.
Results: Supplementation of chow with 0.07% and 0.14% des-fluoro-anacetrapib reduced plasma CETP activity by 81±4.9% and 92±12%, increased plasma apoA-I levels by 38±13% and 47±12%, increased plasma HDL-C levels by 77±24% and 86±13%, and reduced intimal hyperplasia in the injured aortae by 37±11% and 51±10%, respectively (p<0.05 for all). Re-endothelialization of aortic cross sections was assessed by CD31 immunostaining. In the control animals 43±6.7% of the endothelium was CD31+, compared to 69±6.6% and 76±7.7% in the 0.07% and 0.14% des-fluoro-anacetrapib-treated animals, respectively (p<0.05 for both). The enhanced re-endothelialization in the des-fluoro-anacetrapib-treated animals was associated with increased aortic ring relaxation and cGMP production in response to acetylcholine. Relative to control animals, aortic ring relaxation increased by 68±16% and 106±28% at the highest concentration of acetylcholine, while cGMP production increased by 40±11% and 58±15% in the animals treated with 0.07% and 0.14% des-fluoro-anacetrapib, respectively (p<0.05 for all).
Conclusions: The ability of des-fluoro-anacetrapib to regenerate functional endothelium and inhibit intimal hyperplasia in balloon-injured NZW rabbit arteries suggests that CETP inhibition may improve endothelial dysfunction in cardiovascular diseases.
- © 2012 by American Heart Association, Inc.