Background: Silent Information Regulator 1 (SIRT1) is a histone deacetylase that has been associated with protective mechanisms against IRI, but its role in liver transplantation has been poorly investigated. The purpose of this study is to evaluate the possible SIRT1 implication in reduced orthotopic liver transplantation (ROLT) in the rat, as well as to examine a potential relationship between SIRT1 and Losartan, an antagonist of angiotensin II type I receptor (AT1R) antagonist. Methods: Livers of male Sprague-Dawley rats were preserved in University of Wisconsin (UW) storage solution for 1 hour at 4 C and then subjected to ROLT. In an additional group, Losartan was orally administered (5 mg/kg) 24 hours and 1 hour before the surgical procedure to both the donor and the recipient rats respectively. Liver injury (transaminases), SIRT1 protein levels and activity, SIRT3 protein and mRNA expression, endoplasmic reticulum stress (ERS) parameters (GRP78, IRE1a and p-eIf2), heat shock proteins (HO-1, HSP70) expression and apoptosis parameters (Caspase 12 and 3) were measured 24 hours after reperfusion. Results: Here, we demonstrated that Losartan pretreatment diminished hepatic injury in ROLT, which was consistent with induction of both SIRT1 protein expression and activity. Losartan administration provoked also enhanced NAD+ levels, the co-factor necessary for SIRT1 activity. Furthermore, SIRT1 induction by Losartan pre-treatment coincided with decreases in the ERS parameters and in liver apoptosis. Losartan pretreatment also modulated heat shock proteins expression. In addition, both mRNA and protein levels of SIRT3 were comparable in ROLT and Losartan + ROLT group. Conclusions: We evidenced that SIRT1 is induced upon Losartan pretreatment in ROLT and can be considered as an emerging therapeutic strategy in order to diminish hepatic IRI associated to ROLT.

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