Published online before print December 20, 2004, doi: 10.1161/01.CIR.0000151614.22282.F1
(Circulation. 2005;111:44-50.)
© 2005 American Heart Association, Inc.
Coronary Heart Disease |
Cardioprotection by 
-Protein Kinase C Activation From Ischemia
Continuous Delivery and Antiarrhythmic Effect of an 
-Protein Kinase C-Activating Peptide
From the Department of Molecular Pharmacology, Stanford University School of Medicine (K.I., R.B., D.M.-R.), and Department of Cardiovascular Medicine, Stanford University (F.I.), Stanford, Calif.
Correspondence to Daria Mochly-Rosen, Department of Molecular Pharmacology, 269 Campus Dr, 3145 CCSR, Stanford University School of Medicine, Stanford CA 94305-5174. E-mail mochly{at}stanford.edu
Received July 24, 2004; revision received September 10, 2004; accepted September 30, 2004.
Background— We previously showed that a selective activator peptide of -protein kinase C (PKC), 
RACK, conferred cardioprotection against ischemia-reperfusion when delivered ex vivo before the ischemic event. Here, we tested whether in vivo continuous systemic delivery of RACK confers sustained cardioprotection against ischemia-reperfusion in isolated mouse hearts and whether RACK treatment reduces infarct size or lethal arrhythmias in porcine hearts in vivo.
Methods and Results— After RACK was systemically administered in mice either acutely or continuously, hearts were subjected to ischemia-reperfusion in an isolated perfused model. Whereas RACK-induced cardioprotection lasted 1 hour after a single intraperitoneal injection, continuous treatment with RACK induced a sustained preconditioned state during the 10 days of delivery. There was no desensitization to the therapeutic effect, no downregulation of PKC, and no adverse effects after sustained RACK delivery. Porcine hearts were subjected to ischemia-reperfusion in vivo, and RACK was administered by intracoronary injection during the first 10 minutes of ischemia. RACK treatment reduced infarct size (34±2% versus 14±1%, control versus RACK) and resulted in fewer cases of ventricular fibrillation during ischemia-reperfusion (87.5% versus 50%, control versus RACK).
Conclusions— The PKC activator 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 PKC after sustained delivery. Thus, RACK may be useful for patients with ischemic heart disease. In addition, the RACK peptide should be a useful pharmacological agent for animal studies in which systemic and sustained modulation of PKC in vivo is needed.
Key Words: arrhythmia • ischemia • ischemic preconditioning • peptides • protein kinase C
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