Document Detail

Acidosis causes endoplasmic reticulum stress and caspase-12-mediated astrocyte death.
MedLine Citation:
PMID:  15689959     Owner:  NLM     Status:  MEDLINE    
Endoplasmic reticulum (ER) stress leads to activation of caspase-12, which in turn can lead to activation of caspase-3 and cell death. Here we report that transient acidosis induces ER stress and caspase-12-mediated cell death in mouse astrocytes. After a 3-hour incubation at pH 6.0, astrocytes exhibited delayed cell death associated with nuclear condensation and fragmentation. Cell death was reduced by the protein synthesis inhibitor cycloheximide, further suggesting an active cell death program. Acidosis increased the expression of the ER chaperone protein GRP-78, indicative of ER stress. Acidosis also increased caspase-12 mRNA expression, caspase-12 protein expression, cleavage of caspase-12 to its active form, and activation of caspase-3. Each of these effects was suppressed in astrocytes pretreated with caspase-12 antisense phosphorodiamidate morpholino oligodeoxynucleotides (PMOs). Caspase-12 antisense PMOs also reduced the cell death induced by acidosis. Immunoprecipitation studies showed dissociation of both caspase-12 and Ire1-alpha from GRP-78, thereby suggesting a mechanism by which acidosis can initiate the ER stress response. To evaluate caspase-12 activation in vivo, rats were subjected to middle cerebral artery ischemia-reperfusion. Immunostaining of brain sections harvested 24 hours later showed increased caspase-12 expression and nuclear condensation in astrocytes of the periinfarct region exposed to acidosis during ischemia. These findings suggest that acidosis induces ER stress and caspase-12 activation, and that these changes may contribute to delayed cell death after ischemia.
Koji Aoyama; David M Burns; Sang Won Suh; Philippe Garnier; Yasuhiko Matsumori; Hiroaki Shiina; Raymond A Swanson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism     Volume:  25     ISSN:  0271-678X     ISO Abbreviation:  J. Cereb. Blood Flow Metab.     Publication Date:  2005 Mar 
Date Detail:
Created Date:  2005-02-24     Completed Date:  2005-03-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8112566     Medline TA:  J Cereb Blood Flow Metab     Country:  United States    
Other Details:
Languages:  eng     Pagination:  358-70     Citation Subset:  IM    
Department of Neurology, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California, USA.
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MeSH Terms
Acidosis / metabolism*
Astrocytes / metabolism*,  pathology
Caspase 12
Caspase 3
Caspases / drug effects,  genetics,  metabolism*
Cell Death / physiology
Endoplasmic Reticulum / enzymology,  metabolism*
Enzyme Activation
Gene Expression Regulation, Enzymologic
Heat-Shock Proteins / genetics
Hydrogen-Ion Concentration
Molecular Chaperones / genetics
Oligodeoxyribonucleotides, Antisense / pharmacology
RNA, Messenger / genetics,  metabolism
Reg. No./Substance:
0/Casp12 protein, mouse; 0/Casp12 protein, rat; 0/Heat-Shock Proteins; 0/Molecular Chaperones; 0/Oligodeoxyribonucleotides, Antisense; 0/RNA, Messenger; 0/molecular chaperone GRP78; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 12; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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