Document Detail

Myocardial ischemic preconditioning preserves postischemic function of the 26S proteasome through diminished oxidative damage to 19S regulatory particle subunits.
MedLine Citation:
PMID:  20431057     Owner:  NLM     Status:  MEDLINE    
RATIONALE: The ubiquitin proteasome system (UPS) becomes dysfunctional as a result of ischemia/reperfusion (I/R), which may lead to dysregulation of signaling pathways. Ischemic preconditioning (IPC) may prevent dysregulation by preventing UPS dysfunction through inhibition of oxidative damage. OBJECTIVE: Examine the hypothesis that early IPC preserves postischemic UPS function thus facilitating prosurvival signaling events. METHODS AND RESULTS: I/R decreased proteasome chymotryptic activity by 50% in isolated rat heart and an in vivo murine left anterior descending coronary artery occlusion model. Following IPC, proteasome activity was decreased 25% (P<0.05) in isolated heart and not different from baseline in the murine model. Enriched 26S proteasome was prepared and analyzed for protein carbonyl content. Increased (P<0.05) carbonylation in a 53-kDa band following I/R was diminished by IPC. Immunoprecipitation studies indicated that the 53-kDa carbonylation signal was of proteasomal origin. Two-dimensional gel electrophoresis resolved the 53-kDa band into spots analyzed by liquid chromatography/tandem mass spectrometry containing Rpt3/Rpt5 both of which could be immunoprecipitated conjugated to dinitrophenylhydrazine (DNPH). Higher amounts of DNPH-tagged Rpt5 were immunoprecipitated from the I/R samples and less from the IPC samples. I/R increased Bax levels by 63% (P<0.05) which was decreased by IPC. Lactacystin (lac) pretreatment of preconditioned hearts increased Bax by 140% (P<0.05) and also increased ubiquitinated proteins. Pretreatment of hearts with a proteasome inhibitor reversed the effects of IPC on postischemic Rpt5 carbonylation, cardiac function, morphology and morphometry, and ubiquitinated and signaling proteins. CONCLUSIONS: These studies suggest that IPC protects function of the UPS by diminishing oxidative damage to 19S regulatory particle subunits allowing this complex to facilitate degradation of proapoptotic proteins.
Andras Divald; Shaye Kivity; Ping Wang; Edith Hochhauser; Beth Roberts; Saul Teichberg; Aldrin V Gomes; Saul R Powell
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-04-29
Journal Detail:
Title:  Circulation research     Volume:  106     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2010 Jun 
Date Detail:
Created Date:  2010-06-25     Completed Date:  2010-07-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1829-38     Citation Subset:  IM    
FAHA, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
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MeSH Terms
Coronary Occlusion / physiopathology
Heart / physiopathology
Ischemic Preconditioning, Myocardial*
Mice, Inbred Strains
Models, Animal
Myocardial Ischemia / physiopathology*
Oxidative Stress / physiology*
Proteasome Endopeptidase Complex / physiology*
Rats, Sprague-Dawley
Ubiquitin / physiology
bcl-2-Associated X Protein / physiology
Grant Support
Reg. No./Substance:
0/Ubiquitin; 0/bcl-2-Associated X Protein; EC Endopeptidase Complex; EC 3.4.99.-/ATP dependent 26S protease; EC 3.6.1.-/26S proteasome non-ATPase regulatory subunit 13

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