title: Ischemic preconditioning of the murine liver protects through the Akt kinase pathway.
abstract: Hepatic ischemia-reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt-signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20-minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase beta, and caspase-3. In addition, IPC also inhibited the activities of c-Jun N-terminal kinase and nuclear factor kappaB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage.
authors.affiliation: First Department of Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan. izuishi@kms.ac.jp
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Izuishi
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
authors.forename: Mohammad Akram
authors.initials: MA
authors.lastname: Hossain
authors.forename: Masao
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Hisao
authors.initials: H
authors.lastname: Wakabayashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Hajime
authors.initials: H
authors.lastname: Maeta
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000502:physiology*; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D015427:Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D016896:Treatment Outcome; D033921:Vesicular Transport Proteins
chemical_list: D002352:Carrier Proteins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; C527550:Ccdc88a protein, mouse; D033921:Vesicular Transport Proteins