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Reduction of In-Stent Restenosis by Cholesteryl Ester Transfer Protein Inhibition
Ben J Wu1, Yue Li2, Kwok L Ong2
1From the School of Medical Sciences, The University of New South Wales Sydney, Australia (B.J.W., K.L.O., Y.S., S.S., L.H., P.J.B., K.-A.R.); Institute of Pathophysiology and Immunology, Medical University of Graz, Austria (Y.S.); and Merck & Co., Inc, Kenilworth, NJ (D.J.). k.rye@unsw.edu.au ben.wu@unsw.edu.au.
Insights
Inhibiting cholesteryl ester transfer protein activity with des-fluoro-anacetrapib significantly increased high-density lipoprotein (HDL) levels in rabbits. This treatment reduced neointimal hyperplasia and vascular smooth muscle cell proliferation after stenting, offering a potential therapeutic strategy.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Biochemistry
Background:
- Angioplasty and stent implantation are common treatments for atherosclerotic lesions but have high failure rates due to restenosis.
- Restenosis, the re-narrowing of arteries after intervention, is a significant clinical challenge.
- High-density lipoprotein (HDL) levels are inversely correlated with cardiovascular disease risk.
Purpose of the Study:
- To investigate whether increasing plasma HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity prevents stent-induced neointimal hyperplasia.
- To evaluate the effects of des-fluoro-anacetrapib, a CETP inhibitor, on restenosis markers in a rabbit model.
Main Methods:
- New Zealand White rabbits were treated with des-fluoro-anacetrapib or a control diet for 6 weeks.
- Iliac artery endothelial denudation and stent deployment were performed after 2 weeks of treatment.
- Plasma lipid profiles, neointimal hyperplasia, vascular smooth muscle cell proliferation, and migration were assessed.
Main Results:
- Des-fluoro-anacetrapib treatment significantly increased HDL cholesterol and apolipoprotein A-I levels.
- CETP activity was reduced, while non-HDL cholesterol remained unaffected.
- Neointimal area was reduced by 43%, and lumen area increased by 12% post-stenting.
- Vascular smooth muscle cell proliferation was inhibited by 41% in treated animals.
Conclusions:
- Inhibition of CETP activity with des-fluoro-anacetrapib effectively increases HDL levels.
- This approach reduces neointimal hyperplasia and vascular smooth muscle cell proliferation in a stented artery model.
- The observed effects are dependent on scavenger receptor-B1, PDZ domain-containing protein 1, and PI3K/Akt signaling pathways.
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.