A cascade of degradative hydrolase activity contributes to hepatocyte necrosis during anoxia

Amindra S. Arora, Piet De Groen, Yasufumi Emori, Gregory J. Gores

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Calpain proteases contribute to hepatocyte necrosis during anoxia. Our aim was to ascertain the mechanism causing calpain activation during anoxia. In rat hepatocytes, a twofold increase in calpain activity occurred despite the lack of an increase in cytosolic Ca2+ concentration ([Ca2+](i)). The increase in calpain activity was not associated with an increase in calpain mRNA or a decrease in calpastatin mRNA expression. Because phospholipid degradation products generated by phospholipases can activate calpains at physiological [Ca2+](i), we determined the effect of phospholipase inhibitors and activators on calpain activity. Pretreatment of hepatocytes with fluphenazine, a phospholipase inhibitor, decreased calpain activation and improved cell survival. Melittin, a phospholipase A2 activator, increased calpain activity and potentiated cell killing. Finally, phospholipid degradation preceded the increase in calpain activity. Thus the enhanced calpain activity occurring in hepatocytes during anoxia 1) is regulated at the posttranslational level and 2) appears to be dependent on phospholipase activity. These data suggest a novel cascade for degradative hydrolase activity during hepatocyte necrosis by anoxia with phospholipase- mediated activation of calpains.

Original languageEnglish (US)
Pages (from-to)G238-G245
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume270
Issue number2 33-2
DOIs
StatePublished - 1996

Keywords

  • calpain
  • calpastatin
  • fluorescent in situ hybridization
  • fluorogenic calpain substrates
  • phospholipase

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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