Published Online
on December 20, 2004

A more recent version of this article appeared on January 4, 2005

This Article Full Text (PDF) All Versions of this Article: 111/1/44    most recent 01.CIR.0000151614.22282.F1v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inagaki, K. Articles by Mochly-Rosen, D. Search for Related Content PubMed PubMed Citation Articles by Inagaki, K. Articles by Mochly-Rosen, D. Related Collections Cardiovascular Pharmacology Animal models of human disease Arrythmias-basic studies Ischemic biology - basic studies

Submitted on July 24, 2004
Revised on September 10, 2004
Accepted on September 30, 2004

Cardioprotection by -Protein Kinase C Activation From Ischemia. Continuous Delivery and Antiarrhythmic Effect of an -Protein Kinase C-Activating Peptide

Koichi Inagaki MD, PhD, Rebecca Begley PhD, Fumiaki Ikeno MD, and Daria Mochly-Rosen PhD^*

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.

^* To whom correspondence should be addressed. E-mail: mochly{at}stanford.edu.

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

This article has been cited by other articles:

				R. D. Rainbow, R. I. Norman, D. E. Everitt, J. L. Brignell, N. W. Davies, and N. B. Standen Endothelin-I and angiotensin II inhibit arterial voltage-gated K+ channels through different protein kinase C isoenzymes Cardiovasc Res, August 1, 2009; 83(3): 493 - 500. [Abstract] [Full Text] [PDF]

				S. S. Palaniyandi, L. Sun, J. C. B. Ferreira, and D. Mochly-Rosen Protein kinase C in heart failure: a therapeutic target? Cardiovasc Res, May 1, 2009; 82(2): 229 - 239. [Abstract] [Full Text] [PDF]

				E. N. Churchill, M.-H. Disatnik, G. R. Budas, and D. Mochly-Rosen Ethanol for cardiac ischemia: the role of protein kinase c Therapeutic Advances in Cardiovascular Disease, December 1, 2008; 2(6): 469 - 483. [Abstract] [PDF]

				J. Kim, Y.-L. Choi, A. Vallentin, B. S. Hunrichs, M. K. Hellerstein, D. M. Peehl, and D. Mochly-Rosen Centrosomal PKC{beta}II and Pericentrin Are Critical for Human Prostate Cancer Growth and Angiogenesis Cancer Res., August 15, 2008; 68(16): 6831 - 6839. [Abstract] [Full Text] [PDF]

				K. Inagaki, T. Koyanagi, N. C. Berry, L. Sun, and D. Mochly-Rosen Pharmacological Inhibition of {epsilon}-Protein Kinase C Attenuates Cardiac Fibrosis and Dysfunction in Hypertension-Induced Heart Failure Hypertension, June 1, 2008; 51(6): 1565 - 1569. [Abstract] [Full Text] [PDF]

				D. H. Korzick, J. C. Kostyak, J. C. Hunter, and K. W. Saupe Local delivery of PKC{varepsilon}-activating peptide mimics ischemic preconditioning in aged hearts through GSK-3beta but not F1-ATPase inactivation Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2056 - H2063. [Abstract] [Full Text] [PDF]

				I. Khaliulin, S. J. Clarke, H. Lin, J. Parker, M.-S. Suleiman, and A. P. Halestrap Temperature preconditioning of isolated rat hearts - a potent cardioprotective mechanism involving a reduction in oxidative stress and inhibition of the mitochondrial permeability transition pore J. Physiol., June 15, 2007; 581(3): 1147 - 1161. [Abstract] [Full Text] [PDF]

				M. E. Anderson Multiple downstream proarrhythmic targets for calmodulin kinase II: Moving beyond an ion channel-centric focus Cardiovasc Res, March 1, 2007; 73(4): 657 - 666. [Abstract] [Full Text] [PDF]

				F. Ikeno, K. Inagaki, M. Rezaee, and D. Mochly-Rosen Impaired perfusion after myocardial infarction is due to reperfusion-induced {delta}PKC-mediated myocardial damage Cardiovasc Res, March 1, 2007; 73(4): 699 - 709. [Abstract] [Full Text] [PDF]

				K. A. Apple, J. E. McLean, C. E. Squires, B. Schaeffer, J. A. Sample, R. L. Murphy, A. M. Deschamps, A. H. Leonardi, C. M. Allen, J. W. Hendrick, et al. Differential Effects of Protein Kinase C Isoform Activation in Endothelin-Mediated Myocyte Contractile Dysfunction With Cardioplegic Arrest and Reperfusion Ann. Thorac. Surg., August 1, 2006; 82(2): 664 - 671. [Abstract] [Full Text] [PDF]

				A. D. T. Costa, R. Jakob, C. L. Costa, K. Andrukhiv, I. C. West, and K. D. Garlid The Mechanism by Which the Mitochondrial ATP-sensitive K+ Channel Opening and H2O2 Inhibit the Mitochondrial Permeability Transition J. Biol. Chem., July 28, 2006; 281(30): 20801 - 20808. [Abstract] [Full Text] [PDF]

				R. Mukherjee, K. A. Apple, C. E. Squires, B. S. Kaplan, J. E. McLean, S. M. Saunders, R. E. Stroud, and F. G. Spinale Protein Kinase C Isoform Activation and Endothelin-1 Mediated Defects in Myocyte Contractility After Cardioplegic Arrest and Reperfusion Circulation, July 4, 2006; 114(1_suppl): I-308 - I-313. [Abstract] [Full Text] [PDF]

				Z.-Q. Zhao and J. Vinten-Johansen Postconditioning: Reduction of reperfusion-induced injury Cardiovasc Res, May 1, 2006; 70(2): 200 - 211. [Abstract] [Full Text] [PDF]

				K. Inagaki, E. Churchill, and D. Mochly-Rosen Epsilon protein kinase C as a potential therapeutic target for the ischemic heart Cardiovasc Res, May 1, 2006; 70(2): 222 - 230. [Abstract] [Full Text] [PDF]

				K. Yamamura, C. Steenbergen, and E. Murphy Protein kinase C and preconditioning: role of the sarcoplasmic reticulum Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2484 - H2490. [Abstract] [Full Text] [PDF]

				R. Bright and D. Mochly-Rosen The Role of Protein Kinase C in Cerebral Ischemic and Reperfusion Injury Stroke, December 1, 2005; 36(12): 2781 - 2790. [Abstract] [Full Text] [PDF]