Role of SIRT3/FOXO3α signaling pathway in dexmedetomidine-induced reduction of hepatic ischemia-reperfusion injury in mice

Abstract

Objective To evaluate the role of sirtuin 3 (SIRT3)/forkhead box O3α (FOXO3α) signaling pathway in dexmedetomidine-induced reduction of hepatic ischemia-reperfusion (I/R) injury in mice. Methods Forty clean-grade C57BL/6 mice of both sexes, aged 2 weeks, weighing 6-8 g, were divided into 4 groups (n=10 each) using a random number table method: sham operation group (group S), hepatic I/R group (group I/R), dexmedetomidine group (group D) and SIRT3 inhibitor 3-TYP plus dexmedetomidine group (group T+ D). Portal vein and hepatic artery supplying left and middle lobes of the liver and biliary tract were clamped resulting in ischemia of 70% of the liver in anesthetized rats.Normal saline 0.25 ml was intraperitoneally injected at 1 h before establishing model, and 30 min later dexmedetomidine 50 μg/kg (diluted to 0.25 ml in normal saline) was intraperitoneally injected in group D. In group T+ D, 3-TYP 5 mg/kg (diluted to 0.25 ml in normal saline) was intraperitoneally injected at 1 h before establishing model, and 30 min later dexmedetomidine 50 μg/kg (diluted to 0.25 ml in normal saline) was intraperitoneally injected.Mice were selected at 6 h after reperfusion, blood samples were obtained through eyeball, and the mice were then sacrificed and kidneys were removed for determination of the serum concentrations of creatinine (Cr) and blood urea nitrogen (BUN), cell apoptosis (by TUNEL), malondialdehyde (MDA) content (using thiobarbituric acid method), superoxide dismutase (SOD) activity (by xanthine oxidase method), and acetylation of FOXO3α in renal tissues (by using immunoprecipitation) and for examination of the pathologic changes.The damage to renal tubules was scored.Apoptosis index (AI) was calculated. Results Compared with group S, the renal tubular damage score and AI were significantly increased, serum concentrations of Cr and BUN were increased, the content of MDA was increased, the activity of SOD was decreased, and the acetylation of FOXO3α was decreased in I/R, D and T+ D groups (P 0.05). Compared with group D, the renal tubular damage score and AI were significantly increased, serum concentrations of Cr and BUN were increased, the content of MDA was increased, the activity of SOD was decreased, and the acetylation of FOXO3α was decreased in group T+ D (P<0.05). Conclusion Activation of SIRT3/FOXO3α signaling pathway is involved in dexmedetomidine-induced reduction of hepatic I/R injury in mice. Key words: Dexmedetomidine; Sirtuins; Forkhead transcription factors; Reperfusion injury; Liver; Kidney