on July 14, 2003
Circulation. 2003
Published online before print July 14, 2003, doi: 10.1161/01.CIR.0000081943.93653.73
Published online before print July 14, 2003, doi: 10.1161/01.CIR.0000081943.93653.73
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Submitted on February 10, 2003
From the Department of Molecular Pharmacology, Stanford University School of Medicine, Stanford, Calif (K.I., D.M.-R.), and the Department of Internal Medicine, Division of Cardiology, University of Cincinnati Medical Center, Cincinnati, Ohio (H.S.H., G.W.D.). * To whom correspondence should be addressed. E-mail: mochly{at}stanford.edu.
Background--Protein kinase C (PKC) plays a major role in cardioprotection from ischemia/reperfusion injury. Using an HIV-1 Tat protein-derived peptide to mediate rapid and efficient transmembrane delivery of peptide regulators of PKC translocation and function, we examined the cardioprotective effect of selective Methods and Results--In isolated perfused rat hearts, administration of Conclusions--
Revised on April 17, 2003
Accepted on April 18, 2003
Additive Protection of the Ischemic Heart Ex Vivo by Combined Treatment With
Koichi Inagaki MD, PhD, 
-Protein Kinase C Inhibitor and 
-Protein Kinase C Activator
-PKC inhibitor (V1-1) and 
-PKC activator (
RACK) peptides for ischemia/reperfusion damage in isolated perfused rat hearts. Furthermore, we examined the protective effects of these PKC isozymes in isolated perfused hearts subjected to ischemia/reperfusion damage using transgenic mice expressing these peptides specifically in their cardiomyocytes.V1-1 but not RACK during reperfusion improved cardiac function and decreased creatine phosphokinase release. In contrast, pretreatment with RACK but not V1-1, followed by a 10-minute washout before ischemia/reperfusion, also improved cardiac function and decreased creatine phosphokinase release. Furthermore, administration of RACK before ischemia followed by V1-1 during reperfusion only conferred greater cardioprotective effects than that obtained by each peptide treatment alone. Both the -PKC inhibitor and -PKC activator conferred cardioprotection against ischemia/reperfusion injury in transgenic mice expressing these peptides in the heart, and coexpression of both peptides conferred greater cardioprotective effects than that obtained by the expression of each peptide alone.-PKC inhibitor prevents reperfusion injury, and -PKC activator mimics ischemic preconditioning. Furthermore, treatment with both peptides confers additive cardioprotective effects. Therefore, these peptides mediate cardioprotection by regulating ischemia/reperfusion damage at distinct time points.
Key words: ischemia • reperfusion • cardioprotection • enzymes • kinases
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