Introduction. Several studies have shown that intravenous administration of synthetic HDL (sHDL) containing human apoA-I is effective in inducing atherosclerosis regression. A possible limitation of this therapeutic approach may be a rapid apoA-I turnover. Tetranectin-apoA-I, a trimeric human apoA-I, was designed to reduce renal clearance and thus prolong half-life and, possibly, efficacy. Aim of this 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. 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 sHDL containing Tetranectin-apoA-I (TN-sHDL) or with placebo. All rabbits were fasted over-night and blood samples were collected before and at different time points after the infusion. Plaque changes were analyzed in vivo by IVUS, performed before and at the end of the treatment. Animals were sacrificed three days after treatment and carotids were harvested for histology. Total serum cholesterol efflux capacity (CEC) was evaluated using J774 macrophages incubated with cAMP analogue. Results. Total atheroma volume in the placebo group increased between the first and the second IVUS evaluation (+7.09 ± 2.33% from baseline). A slight regression was instead 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). Four hours after the end of the infusion total CEC of serum TN-sHDL was significantly increased compared to baseline (4.49 ± 1.06% vs 8.69 ± 0.72%, p<0.0001). No changes were observed in the placebo group (5.03 ± 0.96% vs 4.48 ± 0.94%, p>0.05). Conclusions. Our results demonstrate that a single infusion of TN-sHDL is effective in reducing carotid plaques 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.

Acute effect of Tetranectin-ApoA-I infusion on atherosclerosis progression/regression in hypercholesterolemic rabbits / G.S. Ganzetti, J. Fingerle, M.P. Adorni, E. Favari, P. Lorenzon, M. Busnelli, S. Manzini, C.R. Sirtori, C. Parolini, G. Chiesa. ((Intervento presentato al 17. convegno International Symposium on Atherosclerosis tenutosi a Amsterdam nel 2015.

Acute effect of Tetranectin-ApoA-I infusion on atherosclerosis progression/regression in hypercholesterolemic rabbits

M. Busnelli;S. Manzini;C.R. Sirtori;C. Parolini;G. Chiesa
2015-05

Abstract

Introduction. Several studies have shown that intravenous administration of synthetic HDL (sHDL) containing human apoA-I is effective in inducing atherosclerosis regression. A possible limitation of this therapeutic approach may be a rapid apoA-I turnover. Tetranectin-apoA-I, a trimeric human apoA-I, was designed to reduce renal clearance and thus prolong half-life and, possibly, efficacy. Aim of this 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. 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 sHDL containing Tetranectin-apoA-I (TN-sHDL) or with placebo. All rabbits were fasted over-night and blood samples were collected before and at different time points after the infusion. Plaque changes were analyzed in vivo by IVUS, performed before and at the end of the treatment. Animals were sacrificed three days after treatment and carotids were harvested for histology. Total serum cholesterol efflux capacity (CEC) was evaluated using J774 macrophages incubated with cAMP analogue. Results. Total atheroma volume in the placebo group increased between the first and the second IVUS evaluation (+7.09 ± 2.33% from baseline). A slight regression was instead 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). Four hours after the end of the infusion total CEC of serum TN-sHDL was significantly increased compared to baseline (4.49 ± 1.06% vs 8.69 ± 0.72%, p<0.0001). No changes were observed in the placebo group (5.03 ± 0.96% vs 4.48 ± 0.94%, p>0.05). Conclusions. Our results demonstrate that a single infusion of TN-sHDL is effective in reducing carotid plaques 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.
Settore BIO/14 - Farmacologia
Settore BIO/16 - Anatomia Umana
Settore BIO/17 - Istologia
Acute effect of Tetranectin-ApoA-I infusion on atherosclerosis progression/regression in hypercholesterolemic rabbits / G.S. Ganzetti, J. Fingerle, M.P. Adorni, E. Favari, P. Lorenzon, M. Busnelli, S. Manzini, C.R. Sirtori, C. Parolini, G. Chiesa. ((Intervento presentato al 17. convegno International Symposium on Atherosclerosis tenutosi a Amsterdam nel 2015.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/795700
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