Ischemic preconditioning of the murine liver protects through the Akt kinase pathway.
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.
Izuishi
Kunihiko
K
First Department of Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan. izuishi@kms.ac.jp
Tsung
Allan
A
Hossain
Mohammad Akram
MA
Fujiwara
Masao
M
Wakabayashi
Hisao
H
Masaki
Tsutomu
T
Billiar
Timothy R
TR
Maeta
Hajime
H
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
D002352:Carrier Proteins; D008840:Microfilament Proteins; D019869:Phosphatidylinositol 3-Kinases; C527550:Ccdc88a protein, mouse; D033921:Vesicular Transport Proteins