Cardioprotection by ε-Protein Kinase C Activation From Ischemia

Abstract

Background— We previously showed that a selective activator peptide of ε-protein kinase C (PKC), ψεRACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of ψεRACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether ψεRACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo. Methods and Results— After ψεRACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas ψεRACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with ψεRACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of εPKC, and no adverse effects after sustained ψεRACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and ψεRACK was administered by intracoronary injection during the first 10 minutes of ischemia. ψεRACK treatment reduced infarct size (34±2% versus 14±1%, control versus ψεRACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus ψεRACK). Conclusions— The εPKC activator ψεRACK 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 εPKC after sustained delivery. Thus, ψεRACK may be useful for patients with ischemic heart disease. In addition, the ψεRACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of εPKC in vivo is needed.