Protective role of silent information regulator 1 against hepatic ischemia: effects on oxidative stress injury, inflammatory response, and MAPKs

Abstract

ABSTRACTObjective: Previous studies have verified that silent information regulator 1 (SIRT1), a class III histone deacetylase, protects against ischemia reperfusion (IR) injury (IRI) in some organs. In this study, we examined whether SIRT1 could protect against hepatic IRI and explored the potential mechanisms.Research design and methods: We examined whether SIRT1 could protect against hepatic IRI in vivo and in vitro using hepatic-specific SIRT1−/- mice, SIRT1 siRNA-transfected hepatocytes and SIRT1+/+ hepatocytes.Results: The expression and activity of SIRT1 were significantly reduced during reperfusion compared with that observed in the control group. Hepatic-specific SIRT1−/- mice exhibited significant increase of hepatic damage markers and augment of oxidative stress and inflammatory response compared with control mice. In vitro studies demonstrated similar results. Furthermore, SIRT1 upregulation protects against hepatic IRI, through the overexpression of p-JNK, p-p38MAPK, and p-ERK. The protection of SIRT1 can be effectively reversed by the inhibitors of p38MAPK, JNK, and ERK.Conclusion: The activation of SIRT1 significantly inhibits the oxidative stress and inflammatory response during hepatic IRI, which can be developed as a novel method to protect against hepatic IRI.