Cardioprotection by epsilon-protein kinase C activation from ischemia: continuous delivery and antiarrhythmic effect of an epsilon-protein kinase C-activating peptide.
BACKGROUND
We previously showed that a selective activator peptide of epsilon-protein kinase C (PKC), psi(epsilon)RACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of psi(epsilon)RACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether psi(epsilon)RACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo.


RESULTS
After psi(epsilon)RACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas psi(epsilon)RACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with psi(epsilon)RACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of epsilonPKC, and no adverse effects after sustained psi(epsilon)RACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and psi(epsilon)RACK was administered by intracoronary injection during the first 10 minutes of ischemia. psi(epsilon)RACK treatment reduced infarct size (34+/-2% versus 14+/-1%, control versus psi(epsilon)RACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus psi(epsilon)RACK).


CONCLUSIONS
The epsilonPKC activator psi(epsilon)RACK induced cardioprotection both in vivo and ex vivo, reduced the incidence of lethal arrhythmia during ischemia-reperfusion, and did not cause desensitization or downregulation of epsilonPKC after sustained delivery. Thus, psi(epsilon)RACK may be useful for patients with ischemic heart disease. In addition, the psi(epsilon)RACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of epsilonPKC in vivo is needed.
Inagaki
Koichi
K
Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, Calif 94305-5174, USA.
Begley
Rebecca
R
Ikeno
Fumiaki
F
Mochly-Rosen
Daria
D
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003331:Coronary Vessels; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D015696:Gene Products, tat / Q000008:administration & dosage; D015918:Infusion Pumps, Implantable; D007269:Injections, Intra-Arterial; D007274:Injections, Intraperitoneal; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000201:enzymology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000008:administration & dosage; D011493:Protein Kinase C / Q000187:drug effects* / Q000378:metabolism; D051744:Protein Kinase C-epsilon; D021381:Protein Transport; D034421:Sus scrofa; D014693:Ventricular Fibrillation / Q000209:etiology / Q000517:prevention & control*; D054322:tat Gene Products, Human Immunodeficiency Virus
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D015696:Gene Products, tat; C477271:His-Asp-Ala-Pro-Ile-Gly-Tyr-Asp; D009842:Oligopeptides; D010446:Peptide Fragments; D054322:tat Gene Products, Human Immunodeficiency Virus; C497137:tat peptide (47-57), Human immunodeficiency virus 1; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon