Ischaemic preconditioning improves proteasomal activity and increases the degradation of PKC during reperfusion

Eric N. Churchill, Julio C. Ferreira, Patricia C. Brum, Luke I. Szweda, Daria Mochly-Rosen

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Aims The response of the myocardium to an ischaemic insult is regulated by two highly homologous protein kinase C (PKC) isozymes, and PKC. Here, we determined the spatial and temporal relationships between these two isozymes in the context of ischaemia/reperfusion (I/R) and ischaemic preconditioning (IPC) to better understand their roles in cardioprotection. Methods and resultsUsing an ex vivo rat model of myocardial infarction, we found that short bouts of ischaemia and reperfusion prior to the prolonged ischaemic event (IPC) diminished PKC translocation by 3.8-fold and increased PKC accumulation at mitochondria by 16-fold during reperfusion. In addition, total cellular levels of PKC decreased by 60 ± 2.7 in response to IPC, whereas the levels of PKC did not significantly change. Prolonged ischaemia induced a 48 ± 11 decline in the ATP-dependent proteasomal activity and increased the accumulation of misfolded proteins during reperfusion by 192 ± 32; both of these events were completely prevented by IPC. Pharmacological inhibition of the proteasome or selective inhibition of PKC during IPC restored PKC levels at the mitochondria while decreasing PKC levels, resulting in a loss of IPC-induced protection from I/R. Importantly, increased myocardial injury was the result, in part, of restoring a PKC-mediated I/R pro-apoptotic phenotype by decreasing pro-survival signalling and increasing cytochrome c release into the cytosol. Conclusion Taken together, our findings indicate that IPC prevents I/R injury at reperfusion by protecting ATP-dependent 26S proteasomal function. This decreases the accumulation of the pro-apoptotic kinase, PKC, at cardiac mitochondria, resulting in the accumulation of the pro-survival kinase, PKC.

Original languageEnglish (US)
Pages (from-to)385-394
Number of pages10
JournalCardiovascular Research
Volume85
Issue number2
DOIs
StatePublished - Jan 2010

Keywords

  • Apoptosis
  • Cardioprotection
  • Ischaemia/reperfusion
  • Ischaemic preconditioning
  • PKC
  • Proteasome

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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