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

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 6 weeks 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 2 weeks of des-fluoro-anacetrapib treatment. The animals were sacrificed 4 weeks 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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.