Circulation. 2003;108:869-875
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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(Circulation. 2003;108:869.)
© 2003 American Heart Association, Inc.
Basic Science Reports |
Additive Protection of the Ischemic Heart Ex Vivo by Combined Treatment With 
-Protein Kinase C Inhibitor and 
-Protein Kinase C Activator
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.).
Correspondence to Daria Mochly-Rosen, PhD, Department of Molecular Pharmacology, Stanford University School of Medicine, CCSR, Room 3145A, 269 Campus Dr, Stanford, CA 94305-5174. E-mail mochly{at}stanford.edu
Received February 10, 2003; revision received April 17, 2003; accepted April 18, 2003.
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 
-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.
Methods and Results— In isolated perfused rat hearts, administration of 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.
Conclusions— -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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