Effect of Tetranectin-ApoA-I infusion on atherosclerosis and HDL-mediated cholesterol efflux capacity in hypercholesterolemic rabbits

Aim. Cholesterol efflux capacity(CEC) is as a functional CV risk biomarker. Intravenous administration of reconstituted-HDL(rHDL) containing h-apoA-I is effective in promoting atherosclerosis regression. Tetranectin-apoA-I(TN), a trimeric h-apoA-I, was designed to reduce renal clearance. Study aim was to evaluate the effect of rHDL containing TN(TN-rHDL) on CEC in relationship to atherosclerosis development. Methods. 18 rabbits underwent a perivascular injury at both carotids, followed by 1.5% cholesterol diet. At 90 days after surgery, rabbits were randomly divided into 2 groups and i.v. treated, for one time, with 200 mg/kg of TN-rHDL or with placebo. Plaque changes were analyzed in vivo by IVUS. Animals were sacrificed three days after the end of the infusion and carotids were harvested for histology. CEC was measured with radioisotopic techniques by using J774-macrophages treated with a cAMP analogue and exposed for 4h to 0.5%(v/v) of rabbit plasma collected before, and 4, 72 h after the end of the infusion. Results. Atheroma volume in the placebo group increased between the first and the second IVUS evaluation. A slight regression was observed vs baseline in TN-rHDL treated group (-0.35±1.97%,p<0.0001 vs placebo). At the maximum plaque burden, TN-rHDL-treated rabbits displayed a lower macrophage content compared to that found in the placebo group (69.5±13.4%vs84.3±9.3%,p< 0.05). Total-CEC at 4h after infusion markedly increased as compared to baseline (4.13±1.17%vs.8.63±0.72%,p<0.0001) and returned back to baseline at 72h. Plasma CEC both via AD and ABCA1 was significantly increased at 4h after infusion with TN-rHDL compared to baseline, whereas no changes were observed after 72h for both efflux pathways. Conclusions. Our results demonstrate that a single infusion of TN-rHDL is effective in reducing carotid plaque progression in hypercholesterolemic rabbits. This effect is associated with a reduction in the plaque macrophage content, and with an improvement in serum CEC, both features leading to a potential stabilization of atherosclerotic plaques.