title: Losartan activates sirtuin 1 in rat reduced-size orthotopic liver transplantation.
abstract: OBJECTIVE
  To investigate a possible association between losartan and sirtuin 1 (SIRT1) in reduced-size orthotopic liver transplantation (ROLT) in rats.
  
  
  METHODS
  Livers of male Sprague-Dawley rats (200-250 g) were preserved in University of Wisconsin preservation solution for 1 h at 4 °C prior to ROLT. In an additional group, an antagonist of angiotensin II type 1 receptor (AT1R), losartan, was orally administered (5 mg/kg) 24 h and 1 h before the surgical procedure to both the donors and the recipients. Transaminase (as an indicator of liver injury), SIRT1 activity, and nicotinamide adenine dinucleotide (NAD(+), a co-factor necessary for SIRT1 activity) levels were determined by biochemical methods. Protein expression of SIRT1, acetylated FoxO1 (ac-FoxO1), NAMPT (the precursor of NAD+), heat shock proteins (HSP70, HO-1) expression, endoplasmic reticulum stress (GRP78, IRE1α, p-eIF2) and apoptosis (caspase 12 and caspase 3) parameters were determined by Western blot. Possible alterations in protein expression of mitogen activated protein kinases (MAPK), such as p-p38 and p-ERK, were also evaluated. Furthermore, the SIRT3 protein expression and mRNA levels were examined.
  
  
  RESULTS
  The present study demonstrated that losartan administration led to diminished liver injury when compared to ROLT group, as evidenced by the significant decreases in alanine aminotransferase (358.3 ± 133.44 vs 206 ± 33.61, P < 0.05) and aspartate aminotransferase levels (893.57 ± 397.69 vs 500.85 ± 118.07, P < 0.05). The lessened hepatic injury in case of losartan was associated with enhanced SIRT1 protein expression and activity (5.27 ± 0.32 vs 6.08 ± 0.30, P < 0.05). This was concomitant with increased levels of NAD(+) (0.87 ± 0.22 vs 1.195 ± 0.144, P < 0.05) the co-factor necessary for SIRT1 activity, as well as with decreases in ac-FoxO1 expression. Losartan treatment also provoked significant attenuation of endoplasmic reticulum stress parameters (GRP78, IRE1α, p-eIF2) which was consistent with reduced levels of both caspase 12 and caspase 3. Furthermore, losartan administration stimulated HSP70 protein expression and attenuated HO-1 expression. However, no changes were observed in protein or mRNA expression of SIRT3. Finally, the protein expression pattern of p-ERK and p-p38 were not altered upon losartan administration.
  
  
  CONCLUSIONS
  The present study reports that losartan induces SIRT1 expression and activity, and that it reduces hepatic injury in a ROLT model.
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Eirini
authors.initials: E
authors.lastname: Pantazi
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bejaoui
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Mohamed Amine
authors.initials: MA
authors.lastname: Zaouali
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Folch-Puy
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Anabela
authors.initials: A
authors.lastname: Pinto Rolo
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Arnau
authors.initials: A
authors.lastname: Panisello
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Carlos Marques
authors.initials: CM
authors.lastname: Palmeira
authors.affiliation: Eirini Pantazi, Mohamed Bejaoui, Mohamed Amine Zaouali, Emma Folch-Puy, Arnau Panisello, Joan Roselló-Catafau, Experimental Pathology Department, Experimental Hepatic Ischemia-Reperfusion Unit, Institute of Biomedical Research of Barcelona (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Roselló-Catafau
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D006360:Heat-Shock Proteins; D012333:RNA, Messenger; D009243:NAD; D020928:Mitogen-Activated Protein Kinases; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D019808:Losartan
keywords: Angiotensin II; Endoplasmic reticulum stress; Liver ischemia reperfusion injury; Losartan; Sirtuin 1