Inhibiting CETP with des-fluoro-anacetrapib doubles capillary density in ischemic rabbit hindlimbs via SR-B1 and PI3K/Akt signaling (Int J Cardiol 2015)

Original title: Increasing HDL levels by inhibiting cholesteryl ester transfer protein activity in rabbits with hindlimb ischemia is associated with increased angiogenesis

Int J Cardiol · 11 July 2015 · 6

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

New Zealand White rabbits fed chow supplemented with 0.07% or 0.14% des-fluoro-anacetrapib for 6 weeks underwent left femoral artery ligation after 2 weeks of treatment, with sacrifice 4 weeks later. The two doses reduced CETP activity by 63 plus or minus 12% and 81 plus or minus 8.6%, raised plasma apoA-I 1.3- and 1.4-fold, and raised HDL cholesterol 1.4- and 1.7-fold. Treatment increased collateral artery number by 60 plus or minus 16% and 84 plus or minus 27%, arteriole wall area by 84 plus or minus 16% and 94 plus or minus 13%, and capillary density in ischemic muscle from 1.1 plus or minus 0.2 in controls to 2.1 plus or minus 0.3 and 2.2 plus or minus 0.4 at the two doses. HDL isolated from treated animals increased tubule formation by human coronary endothelial cells, an effect abolished by knockdown of scavenger receptor-B1 and PDZK1 or by PI3K/Akt inhibition, showing CETP inhibition promotes angiogenesis through this SR-B1- and PI3K/Akt-dependent pathway.

Original abstract

Background: High density lipoprotein (HDL) infusions increase new blood vessel formation (angiogenesis) in rodents with ischemic injury. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity increases angiogenesis in New Zealand White (NZW) rabbits with hindlimb ischemia.

Methods And Results: NZW rabbits were maintained for 6weeks on chow or chow supplemented with 0.07% or 0.14% (wt/wt) of the CETP inhibitor, des-fluoro-anacetrapib. The left femoral artery was ligated after 2weeks of des-fluoro-anacetrapib treatment. The animals were sacrificed 4weeks after femoral artery ligation. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib reduced CETP activity by 63±12% and 81±8.6%, increased plasma apoA-I levels by 1.3±0.1- and 1.4±0.1-fold, and increased plasma HDL-cholesterol levels by 1.4±0.1- and 1.7±0.2-fold, respectively. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib increased the number of collateral arteries by 60±16% and 84±27%, and arteriole wall area in the ischemic hindlimbs by 84±16% and 94±13%, respectively. Capillary density in the ischemic hindlimb adductor muscle increased from 1.1±0.2 (control) to 2.1±0.3 and 2.2±0.4 in the 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib-treated animals, respectively. Incubation of HDLs from des-fluoro-anacetrapib-treated animals with human coronary artery endothelial cells at apoA-I concentrations comparable with their plasma levels increased tubule network formation. These effects were abolished by knockdown of scavenger receptor-B1 (SR-B1) and PDZK1, and pharmacological inhibition of PI3K/Akt.

Conclusion: Increasing HDL levels by inhibiting CETP activity is associated with increased collateral blood vessel formation in NZW rabbits with hindlimb ischemia in an SR-B1- and PI3K/Akt-dependent manner.

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