Inhibiting CETP with des-fluoro-anacetrapib cuts in-stent intimal area by 43% via a scavenger receptor-B1-dependent pathway (ATVB 2017)

Original title: Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition

Arterioscler Thromb Vasc Biol · 12 October 2017 · 6

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

New Zealand White rabbits received normal chow or chow supplemented with 0.14% des-fluoro-anacetrapib, an anacetrapib analog, for 6 weeks, with iliac artery denudation and bare metal stent deployment performed after 2 weeks of treatment and euthanasia 4 weeks post-stenting. Relative to control, des-fluoro-anacetrapib reduced plasma CETP activity and raised apolipoprotein A-I and HDL cholesterol by 53 plus or minus 6.3% and 120 plus or minus 19%, without affecting non-HDL cholesterol. Treatment reduced stented-artery intimal area by 43 plus or minus 5.6% (P less than 0.001), increased luminal area by 12 plus or minus 2.4% (P less than 0.05), and inhibited vascular smooth muscle cell proliferation by 41 plus or minus 4.5% (P less than 0.001). HDL isolated from treated animals directly inhibited human aortic smooth muscle cell proliferation and migration through scavenger receptor-B1, the adaptor protein PDZ domain-containing protein 1, and PI3-kinase/Akt signaling, and also suppressed cytokine-induced proliferation and stent-induced vascular inflammation.

Original abstract

Objective: Angioplasty and stent implantation, the most common treatment for atherosclerotic lesions, have a significant failure rate because of restenosis. This study asks whether increasing plasma high-density lipoprotein (HDL) levels by inhibiting cholesteryl ester transfer protein activity with the anacetrapib analog, des-fluoro-anacetrapib, prevents stent-induced neointimal hyperplasia.

Approach And Results: New Zealand White rabbits received normal chow or chow supplemented with 0.14% (wt/wt) des-fluoro-anacetrapib for 6 weeks. Iliac artery endothelial denudation and bare metal steel stent deployment were performed after 2 weeks of des-fluoro-anacetrapib treatment. The animals were euthanized 4 weeks poststent deployment. Relative to control, dietary supplementation with des-fluoro-anacetrapib reduced plasma cholesteryl ester transfer protein activity and increased plasma apolipoprotein A-I and HDL cholesterol levels by 53±6.3% and 120±19%, respectively. Non-HDL cholesterol levels were unaffected. Des-fluoro-anacetrapib treatment reduced the intimal area of the stented arteries by 43±5.6% (P<0.001), the media area was unchanged, and the arterial lumen area increased by 12±2.4% (P<0.05). Des-fluoro-anacetrapib treatment inhibited vascular smooth muscle cell proliferation by 41±4.5% (P<0.001). Incubation of isolated HDLs from des-fluoro-anacetrapib-treated animals with human aortic smooth muscle cells at apolipoprotein A-I concentrations comparable to their plasma levels inhibited cell proliferation and migration. These effects were dependent on scavenger receptor-B1, the adaptor protein PDZ domain-containing protein 1, and phosphatidylinositol-3-kinase/Akt activation. HDLs from des-fluoro-anacetrapib-treated animals also inhibited proinflammatory cytokine-induced human aortic smooth muscle cell proliferation and stent-induced vascular inflammation.

Conclusions: Inhibiting cholesteryl ester transfer protein activity in New Zealand White rabbits with iliac artery balloon injury and stent deployment increases HDL levels, inhibits vascular smooth muscle cell proliferation, and reduces neointimal hyperplasia in an scavenger receptor-B1, PDZ domain-containing protein 1- and phosphatidylinositol-3-kinase/Akt-dependent manner.

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