Simvastatin ameliorates ionizing radiation-induced apoptosis in the thymus by activating the AKT/sirtuin 1 pathway in mice.

Abstract

Simvastatin is a HMG-CoA reductase inhibitor widely used to lower plasma cholesterol and to protect against cardiovascular risk factors. The aim of this study was to investigate whether simvastatin attenuates ionizing radiation-induced damage in the mouse thymus and to elucidate the possible mechanisms invovled. For this purpose, male C57BL/6J mice aged 6 weeks were used and exposed to 4 Gy 60Co γ-radiation with or without simvastatin (20 mg/kg/day, for 14 days). Apoptosis was determined by terminal deoxynucle-otidyltransferase-mediated dUTP nick-end labeling (TUNEL) assay or transmission electron microscopy (TEM) examination. Thymocytes were also isolated and incubated in DMEM supplemented with 10% FBS at 37°C and exposed to 8 Gy 60Co γ-radiation with or without simvastatin (20 µM). The expression levels of Bcl-2, p53, p-p53, AKT, sirtuin 1 and poly(ADP-ribose) polymerase (PARP) were determined by western blot analysis. TUNEL and TEM examination revealed that simvastatin treatment significantly mitigated ionizing radiation-induced apoptosis in the mouse thymus. It was also found that simvastatin treatment increased AKT/sirtuin 1 expression following exposure to ionizing radiation in vivo and in vitro. In the in vivo model, but not in the in vitro model, Bcl-2 and PARP expression was augmented and that of p53/p-p53 decreased following treatment with simvastatin. On the whole, our findings indicate that simvastatin exerts a protective effect against ionizing radiation-induced damage in the mouse thymus, which may be partially attributed to the activation of the AKT/sirtuin 1 pathway.