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- Title
Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling
- Authors
Zatta, Amanda J.; Kin, Hajime; Lee, George; Wang, Ningping; Jiang, Rong; Lust, Robert; Reeves, James G.; Mykytenko, James; Guyton, Robert A.; Zhao, Zhi-Qing; Vinten-Johansen, Jakob
- Abstract
Abstract: Objective: Using non-selective and selective protein kinase C (PKC) ε and δ isoform inhibitors, we tested the hypothesis that the cardioprotective phenotype invoked by postconditioning (postcon) is dependent on PKC signalling. Furthermore, we determined whether postconditioning alters pPKCε and/or pPKCδ in cytosolic and mitochondrial fractions. Methods: Male Sprague–Dawley rats underwent 30 min left coronary artery (LCA) occlusion followed by 3 h of reperfusion. Rats were randomised to the following groups: Untreated, no intervention either before or after LCA occlusion; Postcon, 3 cycles of 10-s full reperfusion and 10-s re-occlusion, initiated immediately at the onset of reperfusion; Chelerythrine (non-selective PKC inhibitor, 5 mg/kg)±postcon; Rottlerin (PKCδ inhibitor, 0.3 mg/kg)±postcon; KIE1-1 (PKCε inhibitor, 3.8 mg/kg)± postcon. A subset of rats was employed to assess pPKCε and/or pPKCδ in sham, Isch/RP (30-min LCA occlusion followed by 30-min reperfusion), and postcon-treated hearts. Results: Infarct size, expressed as area of necrosis as a percentage of the area at risk, AN/AAR (%), was significantly reduced by postcon compared to control (untreated) rats (39±2% vs. 53±1% in control, P <0.001). Treatment with chelerythrine alone or the PKCε antagonist KIE1-1 alone at reperfusion had no effect on infarct size compared to control. In contrast, the infarct-sparing effect of postcon was abrogated by non-selective PKC inhibition and PKCε antagonism (50±2% and 50±1%, respectively, P <0.002). Inhibition of PKCδ reduced infarct size to values comparable to that in postcon group (36±3% vs. 39±2%). However, postcon in the presence of PKCδ inhibitor did not enhance the infarct-sparing effects (38±2%). In addition, pPKCε in postcon hearts was significantly higher in the total cell homogenate (10338±1627 vs. 4165±608 in Isch/RP, arbitrary units), and pPKCδ translocation to mitochondria was significantly less (>2-fold decrease) compared to Isch/RP. Conclusion: These data suggest that postcon modulates PKC during early reperfusion by increasing PKCε expression and translocation to a site other than the outer mitochondrial membrane, and limits translocation of PKCδ to mitochondria and associated deleterious signalling.
- Subjects
PROTEIN kinase C; MITOCHONDRIA; PROTOPLASM; HEART diseases
- Publication
Cardiovascular Research, 2006, Vol 70, Issue 2, p315
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1016/j.cardiores.2005.11.030