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

摘要

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 deoxynucleotidyltransferase-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.