title: Sirtuin 1-mediated inhibition of p66shc expression alleviates liver ischemia/reperfusion injury.
abstract: OBJECTIVE
  Ischemia/reperfusion is a leading cause of liver damage after surgical intervention, trauma, and transplantation. It has been reported that the nicotinamide adenine dinucleotide-dependent deacetylase sirtuin 1 attenuates myocardial, cerebral, and renal ischemia/reperfusion damage. This study aimed to investigate the involvement of sirtuin 1-mediated p66shc inhibition in liver ischemia/reperfusion and explore the effect of carnosic acid and ischemic preconditioning on liver ischemia/reperfusion-induced damage.
  
  
  METHODS
  Laboratory investigation.
  
  
  METHODS
  University laboratory.
  
  
  METHODS
  Male Sprague-Dawley rats and HepG2 cells.
  
  
  METHODS
  The rats were subjected to 45 minutes of ischemia to 70% of the liver, followed by 3-hour reperfusion. The HepG2 cells were subjected to hypoxia/reoxygenation-induced injury.
  
  
  RESULTS
  In the rats with liver ischemia/reperfusion injury, carnosic acid pretreatment and ischemic preconditioning dramatically reduced the serum aminotransferase activity and proinflammatory chemokine levels and improved the liver histological evaluations. Carnosic acid and ischemic preconditioning also increased manganese superoxide dismutase and Bcl-xL, but down-regulated cleaved caspase-3. Interestingly, the protective effect of carnosic acid and ischemic preconditioning was positively associated with sirtuin 1 activation. By contrast, p66shc, a kinase that promotes oxidative injury and apoptosis, was inhibited by carnosic acid and ischemic preconditioning. Sirtuin 1 small interfering RNA knockdown experiments confirmed that carnosic acid increased sirtuin 1-mediated repression of p66shc in HepG2 cells and that the protective effect of carnosic acid against hypoxia/reoxygenation injury was inhibited by the sirtuin 1 inhibitor nicotinamide. These results suggest that carnosic acid protects hepatocytes from hypoxia/reoxygenation damage through sirtuin 1-mediated p66shc suppression. To support this notion, we further demonstrated that the sirtuin 1 activator resveratrol achieved a protective effect similar to that of carnosic acid against hypoxia/reoxygenation injury, whereas sirtuin 1 small interfering RNA and nicotinamide had the opposite effect.
  
  
  CONCLUSIONS
  Carnosic acid and ischemic preconditioning protect against ischemia/reperfusion-induced liver injury. Mechanistically, the protective effect involves the sirtuin 1-mediated inhibition of p66shc, suggesting that this pathway is a novel potential therapeutic target for protecting the liver from ischemia/reperfusion injury.
authors.affiliation: 1Department of Pharmacology, Dalian Medical University, Dalian, China. 2Department of Pharmacy, Second Affiliated Hospital of Dalian Medical University, Dalian, China. 3Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Yan
authors.forename: Yao
authors.initials: Y
authors.lastname: Jihong
authors.forename: Zhang
authors.initials: Z
authors.lastname: Feng
authors.forename: Xu
authors.initials: X
authors.lastname: Xiaomei
authors.forename: Zhai
authors.initials: Z
authors.lastname: Xiaohan
authors.forename: Wang
authors.initials: W
authors.lastname: Guangzhi
authors.forename: Ma
authors.initials: M
authors.lastname: Zhenhai
authors.forename: Gao
authors.initials: G
authors.lastname: Dongyan
authors.forename: Ma
authors.initials: M
authors.lastname: Xiaochi
authors.forename: Fan
authors.initials: F
authors.lastname: Qing
authors.forename: Liu
authors.initials: L
authors.lastname: Kexin
authors.forename: Tian
authors.initials: T
authors.lastname: Xiaofeng
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D020169:Caspases / Q000097:blood; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D020287:In Situ Nick-End Labeling; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology; D019194:Ischemic Preconditioning; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D009536:Niacinamide / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D000077185:Resveratrol; D055765:Shc Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D056564:Sirtuin 1 / Q000502:physiology*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013267:Stilbenes / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000097:blood; D000637:Transaminases / Q000097:blood
chemical_list: D045784:Abietanes; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D034741:RNA, Small Interfering; D055765:Shc Signaling Adaptor Proteins; C528035:Shc1 protein, rat; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013267:Stilbenes; D009536:Niacinamide; D013482:Superoxide Dismutase; D000637:Transaminases; D020169:Caspases; D056564:Sirtuin 1; C018381:salvin; D000077185:Resveratrol