Document Detail


Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis.
MedLine Citation:
PMID:  19331832     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Acinar cells in pancreatitis die through apoptosis and necrosis, the roles of which are different. The severity of experimental pancreatitis correlates directly with the extent of necrosis and inversely, with apoptosis. Apoptosis is mediated by the release of cytochrome c into the cytosol followed by caspase activation, whereas necrosis is associated with the mitochondrial membrane potential (DeltaPsim) loss leading to ATP depletion. Here, we investigate the role of Bcl-2 proteins in apoptosis and necrosis in pancreatitis. We found up-regulation of prosurvival Bcl-2 proteins in pancreas in various experimental models of acute pancreatitis, most pronounced for Bcl-xL. This up-regulation translated into increased levels of Bcl-xL and Bcl-2 in pancreatic mitochondria. Bcl-xL/Bcl-2 inhibitors induced DeltaPsim loss and cytochrome c release in isolated mitochondria. Corroborating the results on mitochondria, Bcl-xL/Bcl-2 inhibitors induced DeltaPsim loss, ATP depletion and necrosis in pancreatic acinar cells, both untreated and hyperstimulated with CCK-8 (in vitro pancreatitis model). Together Bcl-xL/Bcl-2 inhibitors and CCK induced more necrosis than either treatment alone. Bcl-xL/Bcl-2 inhibitors also stimulated cytochrome c release in acinar cells leading to caspase-3 activation and apoptosis. However, different from their effect on pronecrotic signals, the stimulation by Bcl-xL/Bcl-2 inhibitors of apoptotic responses was less in CCK-treated than control cells. Therefore, Bcl-xL/Bcl-2 inhibitors potentiated CCK-induced necrosis but not apoptosis. Correspondingly, transfection with Bcl-xL siRNA stimulated necrosis but not apoptosis in the in vitro pancreatitis model. Further, in animal models of pancreatitis Bcl-xL up-regulation inversely correlated with necrosis, but not apoptosis. Results indicate that Bcl-xL and Bcl-2 protect acinar cells from necrosis in pancreatitis by stabilizing mitochondria against death signals. We conclude that Bcl-xL/Bcl-2 inhibition would aggravate acute pancreatitis, whereas Bcl-xL/Bcl-2 up-regulation presents a strategy to prevent or attenuate necrosis in pancreatitis.
Authors:
Kai-Feng Sung; Irina V Odinokova; Olga A Mareninova; Zoltán Rakonczay; Péter Hegyi; Stephen J Pandol; Ilya Gukovsky; Anna S Gukovskaya
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2009-01-24
Journal Detail:
Title:  Experimental cell research     Volume:  315     ISSN:  1090-2422     ISO Abbreviation:  Exp. Cell Res.     Publication Date:  2009 Jul 
Date Detail:
Created Date:  2009-06-01     Completed Date:  2009-06-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0373226     Medline TA:  Exp Cell Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1975-89     Citation Subset:  IM    
Affiliation:
Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphate / metabolism
Animals
Base Sequence
Caerulein / toxicity
Capsid Proteins
Caspase 3 / metabolism
Cytochromes c / metabolism
DNA Primers / genetics
Disease Models, Animal
Gene Expression
Male
Membrane Potential, Mitochondrial / drug effects
Mice
Mitochondria / drug effects,  metabolism*
Necrosis
Pancreas / drug effects,  metabolism,  pathology
Pancreatitis, Acute Necrotizing / genetics,  metabolism*,  pathology*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors,  metabolism*
RNA, Messenger / genetics,  metabolism
Rats
Rats, Sprague-Dawley
Sincalide / pharmacology
bcl-X Protein / antagonists & inhibitors,  genetics,  metabolism
Grant Support
ID/Acronym/Agency:
DK59936/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Bcl2l1 protein, mouse; 0/Bcl2l1 protein, rat; 0/Capsid Proteins; 0/DNA Primers; 0/Proto-Oncogene Proteins c-bcl-2; 0/RNA, Messenger; 0/VP3 protein, Chicken anemia virus; 0/bcl-X Protein; 17650-98-5/Caerulein; 25126-32-3/Sincalide; 56-65-5/Adenosine Triphosphate; 9007-43-6/Cytochromes c; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3

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