Hypoxia activates c-jun N-terminal kinase via Rac1-dependent reactive oxygen species production in hepatocytes

Kevin P. Mollen, Carol A. McCloskey, Hiroyuki Tanaka, Jose M. Prince, Ryan M. Levy, Brian S. Zuckerbraun, Timothy R. Billiar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Scopus citations


The earliest events after the induction of hemorrhagic shock (HS) are complex and poorly understood. We have recently demonstrated that decreased tissue perfusion and hypoxia during HS lead to an increased phosphorylation of c-Jun N-terminal kinase (JNK) in vivo. The purpose of these investigations was to test the hypothesis that hypoxia activates JNK via Rac1-dependent reactive oxygen species (ROS) signaling. Mice subjected to HS and resuscitated with Ringer's ethyl pyruvate solution (REPS) or N-acetylcysteine (NAC), two scavengers of ROS, demonstrated decreased levels of phosphorylated JNK. Exposure of primary mouse hepatocytes in culture to 1% oxygen led to increased production of ROS and phosphorylation of JNK. The duration of hypoxia correlated with the level of generation of ROS and JNK activation. The phosphorylation of JNK was attenuated in the presence of ROS scavengers or the nicotinamide adenosine dinucleotide phosphate [NDA(P)H] oxidase inhibitor, diphenyleneiodonium (DPI). In addition, hypoxia increased activation of Rac1. Inhibition of Rac1 activation by adenoviral gene transfer of dominant-negative Rac1 (AdRac1) attenuated both ROS formation and JNK activation. Together, these data suggest that ROS generation during hypoxia in the liver directly leads to JNK activation in a Rac1-dependent process.

Original languageEnglish
Pages (from-to)270-277
Number of pages8
Issue number3
StatePublished - Sep 2007
Externally publishedYes


  • Hemorrhagic shock
  • Hypoxia
  • Rac1
  • Reactive oxygen species
  • Ringer's ethyl pyruvate solution
  • c-Jun N-terminal-kinase


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