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Myocardial ischemic preconditioning preserves postischemic function of the 26S proteasome through diminished oxidative damage to 19S regulatory particle subunits.

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.

Pubmed ID: 20431057


  • Divald A
  • Kivity S
  • Wang P
  • Hochhauser E
  • Roberts B
  • Teichberg S
  • Gomes AV
  • Powell SR


Circulation research

Publication Data

June 25, 2010

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL68936

Mesh Terms

  • Animals
  • Coronary Occlusion
  • Heart
  • Ischemic Preconditioning, Myocardial
  • Male
  • Mice
  • Mice, Inbred Strains
  • Models, Animal
  • Myocardial Ischemia
  • Oxidative Stress
  • Proteasome Endopeptidase Complex
  • Rats
  • Rats, Sprague-Dawley
  • Ubiquitin
  • bcl-2-Associated X Protein