Introduction. Experimental and clinical studies have shown that intravenous administration of synthetic HDL (sHDL) containing human apoA-I is effective in inducing atherosclerosis regression. However, one main drawback of this therapeutic approach may be a rapid apoA-I turnover. To circumvent this problem, a recombinant high-molecular mass variant of human apoA-I, named Tetranectin-apoA-I, has been engineered by fusing three apoA-I molecules with the trimerization domain of human. This trimeric apoA-I does not pass the glomerular filters and hence shows a prolonged half-life as compared to normal apoA-I. Aim of the present study was to evaluate the effect of Tetranectin-apoA-I infusion on atherosclerosis in a rabbit model, widely used to test the efficacy of sHDL. Methods. The study was performed on 18 male New Zealand white rabbits. To induce lipid-rich plaque formation, common carotid arteries were perivascularly injured and, starting from the day of the surgery, all animals were fed a 1.5% cholesterol diet for the whole duration of the study. 90 days after lesion induction, rabbits were randomly divided into 2 groups and i.v. treated, for one time, with 200 mg/kg of sHDL containing Tetranectin-apoA-I (TN-sHDL) or with placebo. All animals were fasted over-night and blood samples were collected before and at different time points after the end of the infusion for biochemical evaluations. Plaque changes were analyzed in vivo by intravascular intrasound (IVUS), performed before and three days after the treatment, i.e. at sacrifice. Animals were then sacrificed and carotids were harvested for histological analyses. Aqueous diffusion (AD) - dependent - and total-cholesterol efflux capacity (CEC) of rabbit plasma, collected before infusion, and at 4h and 72h after the end of the treatment,were evaluated using J774 murine macrophages. Results. Total atheroma volume in the placebo group increased in the time between the first and the second IVUS evaluation (+7.09±2.33% from baseline). On the contrary a slight regression was observed vs baseline in TN-sHDL treated group (-0.35±1.97%, p<0.0001 vs placebo). At the maximum plaque burden, TN-sHDL treated rabbits displayed a significant lower macrophage content compared to that found in the placebo group (69.5±13.4% vs 84.3±9.3%, p<0.05). Starting from 2 min after the end of the infusion and up to 24 h, a significant increase in plasma free cholesterol was observed in rabbits treated with TN-sHDL (p<0.05 vs placebo). Moreover, four hours after the end of the infusion both AD-dependent-and total-CEC of TN-sHDL-plasma were significantly increased compared to that of placebo (3.35±0.56% vs 1.68±0.08% for AD-dependent-CEC, p<0.005, and 9.02±0.61% vs 4.43±0.58%, for total-CEC, p<0.00001). Conclusions. Taken together our results demonstrate that a single intravenous infusion of TN-sHDL is able to inhibit carotid plaque progression in hypercholesterolemic rabbits. This effect was associated with a reduction in plaque macrophage content, and a rise in both CEC and free cholesterol plasma concentration. The present data indicate that administration of TN-sHDL could potentially be a pharmacological approach for rapid plaque stabilization.
|Titolo:||A single infusion of trimeric apoA-I in hypercholesterolemic rabbits stabilizes atherosclerotic plaques and increases plasma cholesterol efflux capacity|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
|Data di pubblicazione:||2015|
|Enti collegati al convegno:||Società Italiana per lo Studio dell'Arteriosclerosi|
|Appare nelle tipologie:||01 - Articolo su periodico|