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. METHODS AND 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.
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. METHODS AND 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.
Authors: Thomas J Hund; Deborah L Lerner; Kathryn A Yamada; Richard B Schuessler; Jeffrey E Saffitz Journal: Heart Rhythm Date: 2007-06-08 Impact factor: 6.343