A cascade of degradative hydrolase activity contributes to
hepatocyte necrosis during anoxia.
Arora, Amindra S., Piet De Groen, Yasufumi Emori, Gregory J. Gores.
Center for Basic Research in Digestive Diseases, Division of
Gastroenterology and Internal Medicine, Mayo Clinic and Foundation,
Rochester, MN 55905, Department of Biophysics and Biochemistry,
Faculty of Science, University of Tokyo, Hongo 7-3-1, Bunkyo-Ku,
Tokyo, Japan
APStracts 2:0152G, 1995.
Calpain proteases contribute to hepatocyte necrosis during anoxia. Our
aims were to ascertain the mechanism causing calpain activation
during anoxia. In rat hepatocytes, a 2-fold increase in calpain
activity occurred despite the lack of an increase in Ca++i. The
increase in calpain activity was not associated with an increase in
calpain mRNA nor a decrease in calpastatin mRNA expression. Because
phospholipid degradation products generated by phospholipases can
activate calpains at physiologic Ca+2i, 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 post-translational 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.
Received 12 May 1995; accepted in final form 19 July 1995.
APS Manuscript Number G202-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 August 1995.