Copyright © 2006, European Society of Cardiology
Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling
aDepartment of Cardiothoracic Surgery, Carlyle Fraser Heart Centre/Crawford Long Hospital, Emory University School of Medicine, Atlanta, GA 30308-2225, United States
bDepartment of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC 27858-4353, United States
* Corresponding author. Cardiothoracic Research Laboratory, Crawford Long Hospital 550 Peachtree Street, NE, Atlanta, GA 30308-2225, United States. Tel.: +1 404 686 2511; fax: +1 404 686 4888. Email address: azatta{at}emory.edu
Objective Using non-selective and selective protein kinase C (PKC) 
and 
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 pPKC and/or pPKC 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 (PKC inhibitor, 0.3 mg/kg)±postcon; KIE1-1 (PKC inhibitor, 3.8 mg/kg)± postcon. A subset of rats was employed to assess pPKC and/or pPKC 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 PKC 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 PKC antagonism (50±2% and 50±1%, respectively, P<0.002). Inhibition of PKC reduced infarct size to values comparable to that in postcon group (36±3% vs. 39±2%). However, postcon in the presence of PKC inhibitor did not enhance the infarct-sparing effects (38±2%). In addition, pPKC in postcon hearts was significantly higher in the total cell homogenate (10338±1627 vs. 4165±608 in Isch/RP, arbitrary units), and pPKC 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 PKC expression and translocation to a site other than the outer mitochondrial membrane, and limits translocation of PKC to mitochondria and associated deleterious signalling.
KEYWORDS Postconditioning; Myocardial infarction; Mitochondria; Protein kinase C; Protein phosphorylation; Reperfusion injury
Time for primary review 25 days
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