Title

 

Authors

I. Zanotti¹, G. Stomeo¹, D. Greco¹, G. Lusardi¹, F. Zimetti¹, F. Potì² and F. Bernini<sup>1

1</sup>Dept. of Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, Parma, Italy
²Dept. of Medicine, Endocrinology, Metabolism and Geriatry, University of Modena e Reggio Emilia, Modena, Italy 

 

Abstract

Increased susceptibility to cardiovascular disease is a major concern for the use of immunosuppressive agents in organ transplanted patients. The process of reverse cholesterol transport (RCT) exerts an antiatherosclerotic activity by driving the release of cholesterol from peripheral cells to the liver for the ultimate elimination into the feces. We investigated whether the immunosuppressive drug cyclosporine A (CsA) may influence the RCT in vivo. RCT was measured in C57BL/6J mice treated for 14 days with CsA 50mg/kg/day or vehicle and i.p. injected with ³H-cholesterol-loaded macrophages, in order to trace cholesterol mobilization along the RCT pathway from macrophages to plasma, liver and feces. CsA did not affect plasma levels of total cholesterol, HDL-cholesterol or triglycerides, but significantly increased the amount of radioactive cholesterol in plasma (% cpm /cpm injected±s.d: 2.1%±1.2 vs 1.2%±1.0; p<0.05). Whereas no difference was detected in the ³H-cholesterol content in the liver (4.2%± 1.0 vs  4.4%± 0.6 for vehicle and CsA-treated mice respectively), less radioactivity was found in the feces of CsA-treated animals compared to control (0.36%±0.05 vs 0.63%±0.12; p<0.05). CsA produced an increase of plasma capacity to drive cholesterol efflux from macrophages with a mechanism mediated by ATP Binding Cassette A1 (ABCA1), the most relevant lipid transporter in cells (1.12%±0.41 vs 2.91%±1.1 for vehicle and CsA-treated mice respectively; p<0.05). Conversely, CsA did not affect cholesterol efflux that occurs via Scavenger Receptor Class B Type I-, ATP Binding Cassette G1-  or passive diffusion-mediated pathways. In conclusion, CsA treatment in mice induced a significant reduction of fecal sterol excretion. This effect, together with the promotion of ABCA1-mediated plasma efflux potential, results in the accumulation of cholesterol in the plasma compartment. Further investigations are necessary to provide insights into the mechanisms accounting for the impairment of the process. However, this initial observation may provide a potential mechanism for the high incidence of atherosclerotic coronary artery disease following organ transplantation.