Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes

Jay Raval, Suzanne Lyman, Takashi Nitta, Dagmara Mohuczy, John J. Lemasters, Jae Sung Kim, Kevin E. Behrns

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Hepatocytes from cirrhotic murine livers exhibit increased basal ROS activity and resistance to TGFβ-induced apoptosis, yet when ROS levels are decreased by antioxidant pretreatment, these cells recover susceptibility to apoptotic stimuli. To further study these redox events, hepatocytes from cirrhotic murine livers were pretreated with various antioxidants prior to TGFβ treatment and the ROS activity, apoptotic response, and mitochondrial ROS generation were assessed. In addition, normal hepatocytes were treated with low-dose H2O2 and ROS and apoptotic responses determined. Treatment of cirrhotic hepatocytes with various antioxidants decreased basal ROS and rendered them susceptible to apoptosis. Examination of normal hepatocytes by confocal microscopy demonstrated colocalization of ROS activity and respiring mitochondria. Basal assessment of cirrhotic hepatocytes showed nonfocal ROS activity that was abolished by antioxidants. After pretreatment with an adenovirus expressing MnSOD, basal cirrhotic hepatocyte ROS were decreased and TGFβ-induced colocalization of ROS and mitochondrial respiration was present. Treatment of normal hepatocytes with H2O2 resulted in a sustained increase in ROS and resistance to TGFβ apoptosis that was reversed when these cells were pretreated with an antioxidant. In conclusion, cirrhotic hepatocytes have a nonfocal distribution of ROS. However, normal and cirrhotic hepatocytes exhibit mitochondrial localization of ROS that is necessary for apoptosis.

Original languageEnglish
Pages (from-to)1645-1654
Number of pages10
JournalFree Radical Biology and Medicine
Volume41
Issue number11
DOIs
StatePublished - Dec 1 2006

Keywords

  • Apoptosis
  • Hepatocytes
  • Mitochondria
  • Reactive oxygen species (ROS)
  • Transforming growth factor beta (TGFβ)

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