Inhibition of delta-protein kinase C protects against reperfusion injury of the ischemic heart in vivo.
BACKGROUND
Current treatment for acute myocardial infarction (AMI) focuses on reestablishing blood flow (reperfusion). Paradoxically, reperfusion itself may cause additional injury to the heart. We previously found that delta-protein kinase C (deltaPKC) inhibition during simulated ischemia/reperfusion in isolated rat hearts is cardioprotective. We focus here on the role for deltaPKC during reperfusion only, using an in vivo porcine model of AMI.


RESULTS
An intracoronary application of a selective deltaPKC inhibitor to the heart at the time of reperfusion reduced infarct size, improved cardiac function, inhibited troponin T release, and reduced apoptosis. Using 31P NMR in isolated perfused mouse hearts, we found a faster recovery of ATP levels in hearts treated with the deltaPKC inhibitor during reperfusion only.


CONCLUSIONS
Reperfusion injury after cardiac ischemia is mediated, at least in part, by deltaPKC activation. This study suggests that including a deltaPKC inhibitor at reperfusion may improve the outcome for patients with AMI.
Inagaki
Koichi
K
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, Calif 94305-5174, USA.
Chen
Leon
L
Ikeno
Fumiaki
F
Lee
Felix H
FH
Imahashi
Ken-ichi
K
Bouley
Donna M
DM
Rezaee
Mehrdad
M
Yock
Paul G
PG
Murphy
Elizabeth
E
Mochly-Rosen
Daria
D
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D006328:Cardiac Catheterization; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D007261:Infusions, Intra-Arterial; D051379:Mice; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D010725:Phosphocreatine / Q000032:analysis; D010758:Phosphorus / Q000032:analysis; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D051745:Protein Kinase C-delta; D013552:Swine; D020107:Troponin T / Q000032:analysis
D015415:Biomarkers; D004791:Enzyme Inhibitors; D009842:Oligopeptides; C477270:Ser-Phe-Asn-Ser-Tyr-Glu-Leu-Gly-Glu-Ser-Leu; D020107:Troponin T; D010725:Phosphocreatine; D010758:Phosphorus; C497259:Prkcd protein, mouse; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases