An anacetrapib analog cuts CETP activity by 89% and reduces neointimal hyperplasia in bypassed rabbit veins by 38% (Sci Rep 2019)

Coronary artery bypass grafting is among the most commonly performed of all cardiovascular surgical procedures. However, graft failure due to stenosis reduces the long-term benefit of the intervention. This study asks if elevating plasma high density lipoprotein cholesterol (HDL-C) levels by inhibition of cholesteryl ester transfer protein (CETP) activity with des-fluoro-anacetrapib, an analog of the CETP inhibitor anacetrapib, prevents vein bypass-induced neointimal hyperplasia. NZW rabbits were placed on a normal chow diet or chow containing 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Bypass grafting of the jugular vein to the common carotid artery was performed 2 weeks after starting dietary des-fluoro-anacetrapib supplementation. The animals were euthanised 4 weeks post-bypass grafting. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma CETP activity by 89 ± 6.9%, increased plasma apolipoprotein A-I levels by 24 ± 5.5%, increased plasma HDL-C levels by 93 ± 26% and reduced intimal hyperplasia in the grafted vein by 38 ± 6.2%. Des-fluoro-anacetrapib treatment was also associated with decreased bypass grafting-induced endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), endothelial dysfunction, and smooth muscle cell (SMC) proliferation in the grafted vein. In conclusion, increasing HDL-C levels by inhibiting CETP activity is associated with inhibition of intimal hyperplasia in grafted veins, reduced inflammatory responses, improved endothelial function, and decreased SMC proliferation.