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.

Sexual Dimorphism of Gut Microbiota Dictates Therapeutics Efficacy of Radiation Injuries

“…We further used simvastatin, atorvastatin, and rosuvastatin to block lipid metabolism, only simvastatin protected male mice against radiation‐induced toxicity. Of note, simvastatin had been reported to mitigate radiation‐induced organ injuries, covering small intestine and hematopoiesis system . However, the mice in these studies were exposed to total body irradiation only which caused acute hematopoietic syndrome not GI syndrome.…”

“…Thus, whether therapeutic approaches for radiation‐caused toxicity representing sexual dimorphism remains poorly understood, which possesses pivotal clinical value. As a HMG‐CoA reductase inhibitor and an anticholesterol drug, simvastatin has also been reported to mitigate radiation toxicity . However, the evolution of males and females facilitates comprehension of sex‐specific physiology and, consequently, differential susceptibility to diseases with particular reference to those involving energy metabolism .…”

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“…In this study, C57BL/6J mice were pretreated with simvastatin (20 mg/kg) on three different days in a seven-day cycle. Simvastatin intensified the expression of Bcl-2 and PARP and reduced p53/p-p53 [ 88 ]. In 2013, Kok et al investigated the effects of simvastatin in collagen-induced arthritis (CAI) and reported that simvastatin downregulated TNF-α expression and CCL20 production.…”

Myocardial Ischemia Related to Common Cancer Therapy—Prevention Insights

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