Ischemic preconditioning of the murine liver protects through the Akt kinase pathway

Kunihiko Izuishi*, Allan Tsung, Mohammad Akram Hossain, Masao Fujiwara, Hisao Wakabayashi, Tsutomu Masaki, Timothy R. Billiar, Hajime Maeta

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

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 β, and caspase-3. In addition, IPC also inhibited the activities of c-Jun N-terminal kinase and nuclear factor κβ 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.

Original languageEnglish
Pages (from-to)573-580
Number of pages8
JournalHepatology
Volume44
Issue number3
DOIs
StatePublished - Sep 2006
Externally publishedYes

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