Cardioprotection by ε-protein kinase C activation from ischemia -: Continuous delivery and antiarrhythmic effect of an ε-protein kinase C-activating peptide

Background - We previously showed that a selective activator peptide of epsilon-protein kinase C (PKC), psiepsilonRACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of psiepsilonRACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether psiepsilonRACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo. Methods and Results - After psiepsilonRACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas psiepsilonRACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with psiepsilonRACK 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 psiepsilonRACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and psiepsilonRACK was administered by intracoronary injection during the first 10 minutes of ischemia. psiepsilonRACK treatment reduced infarct size (34+/-2% versus 14+/-1%, control versus psiepsilonRACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus psiepsilonRACK). Conclusions - The epsilonPKCactivator psiepsilonRACK 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, psiepsilonRACK may be useful for patients with ischemic heart disease. In addition, the psiepsilonRACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of epsilonPKC in vivo is needed.