The divergent roles of protein kinase C epsilon and delta in simulated ischaemia-reperfusion injury in human myocardium.
Experimental studies suggest that cardioprotection can be achieved through either the activation of PKC-epsilon prior to the index ischaemic episode or the inhibition of PKC-delta at the onset of reperfusion. However, whether these PKC isoforms exert such divergent roles in human myocardium, subjected to simulated ischaemia-reperfusion injury, is unclear. Human atrial trabeculae were isolated from right atrial appendages harvested from patients undergoing elective cardiac surgery. These were subjected to 90 min of hypoxia followed by 120 min of reoxygenation, at the end of which the recovery of baseline contractile function was determined. Atrial trabeculae were randomised to receive various treatment protocols comprising a peptide activator of PKC-epsilon, a peptide inhibitor of PKC-delta and their respective inactive control peptides. Administering the PKC-delta peptide inhibitor at reoxygenation improved the recovery of function at all the concentrations tested (39.3+/-1.4% at 5 nM, 52.4+/-2.9% at 50 nM and 46.8+/-2.9% at 500 nM versus the control group, 27.5+/-1.4%: N > or = 6/group: P<0.02). Preconditioning with the PKC-epsilon peptide activator improved the recovery of function (40.0+/-0.8% at 50 nM and 49.7+/-3.1% at 500 nM versus the control group 27.5+/-1.4%: N > or = 6/group: P<0.02). This cardioprotective effect was comparable to that achieved by a standard hypoxic preconditioning protocol (52.3+/-3.2%). Interestingly, administering the PKC-epsilon activator (500 nM) at the onset of reperfusion also improved the recovery of contractile function (40.7+/-2.1% versus 27.5+/-1.5%: N > or = 6/group: P < 0.05). In human myocardium, cardioprotection can be achieved by either inhibiting PKC-delta or activating PKC-epsilon at the onset of reperfusion. In addition, PKC-epsilon activation offers cardioprotection when administered as a preconditioning strategy.
Sivaraman
Vivek
V
The Hatter Institute and Centre for Cardiology, University College London Hospital, 67 Chenies Mews, London WC1E6HX, UK.
Hausenloy
Derek J
DJ
Kolvekar
Shyam
S
Hayward
Martin
M
Yap
John
J
Lawrence
David
D
Di Salvo
Carmelo
C
Yellon
Derek M
DM
D000328:Adult; D000368:Aged; D004789:Enzyme Activation; D006801:Humans; D066298:In Vitro Techniques; D008875:Middle Aged; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000517:prevention & control; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D020127:Recovery of Function
D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon