Circulation Research. 2004;95:230-232
Published online before print July 8, 2004, doi: 10.1161/01.RES.0000138303.76488.fe
Published online before print July 8, 2004, doi: 10.1161/01.RES.0000138303.76488.fe
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© 2004 American Heart Association, Inc.
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Postconditioning: A Form of "Modified Reperfusion" Protects the Myocardium by Activating the Phosphatidylinositol 3-Kinase-Akt Pathway
From The Hatter Institute and Centre for Cardiology, University College London Hospital, London, UK.
Correspondence to Derek M. Yellon, PhD, DSc Hon FRCP, The Hatter Institute and Centre for Cardiology, University College London Hospital, Grafton Way, London, WC1E 6DB, UK. E-mail hatter-institute{at}ucl.ac.uk
Abstract
Brief intermittent episodes of ischemia and reperfusion, at the onset of reperfusion after a prolonged period of ischemia, confer cardioprotection, a phenomenon termed "ischemic postconditioning" (Postcond). We hypothesized that this phenomenon may just represent a modified form of reperfusion that activates the reperfusion injury salvage kinase (RISK) pathway. Isolated perfused rat hearts were subjected to: (a) 35 minutes of ischemia and 120 minutes of reperfusion, and infarct size was determined by tetrazolium staining; or (b) 35 minutes of ischemia and 7 minutes of reperfusion, and the phosphorylation states of Akt, endothelial NO synthase (eNOS), and p70S6K were determined. Postcond reduced infarct size from 51.2±3.4% to 31.5±4.1% (P<0.01), an effect comparable with ischemic preconditioning (IPC; 27.5±2.3%; P<0.01). Of interest, the combined protective effects of IPC and Postcond were not additive (30.1±4.8% with IPC+Postcond; P=NS). Inhibiting phosphatidylinositol 3-kinase (PI3K) at reperfusion using LY or Wortmannin (Wort) during the first 15 minutes of reperfusion completely abolished Postcond-induced protection (31.5±4.1% with Postcond versus 51.7±4.5% with Postcond+LY, P<0.01; 56.2±10.1% with Postcond+ Wort; P<0.01), suggesting that Postcond protects the heart by activating PI3K-Akt. Western blot analysis demonstrated that Postcond induced a significant increase in phosphorylation of Akt, eNOS, and p70S6K in an LY- and Wort-sensitive manner. In conclusion, we show for the first time that ischemic Postcond protects the myocardium by activating the prosurvival kinases PI3K-Akt, eNOS, and p70S6K in accordance with the RISK pathway.
Key Words: ischemia • cardioprotection • reperfusion • postconditioning • kinases
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O. Gateau-Roesch, L. Argaud, and M. Ovize Mitochondrial permeability transition pore and postconditioning Cardiovasc Res, May 1, 2006; 70(2): 264 - 273. [Abstract] [Full Text] [PDF]
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S. Philipp, X.-M. Yang, L. Cui, A. M. Davis, J. M. Downey, and M. V. Cohen Postconditioning protects rabbit hearts through a protein kinase C-adenosine A2b receptor cascade Cardiovasc Res, May 1, 2006; 70(2): 308 - 314. [Abstract] [Full Text] [PDF]
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A. J. Zatta, H. Kin, G. Lee, N. Wang, R. Jiang, R. Lust, J. G. Reeves, J. Mykytenko, R. A. Guyton, Z.-Q. Zhao, et al. Infarct-sparing effect of myocardial postconditioning is dependent on protein kinase C signalling Cardiovasc Res, May 1, 2006; 70(2): 315 - 324. [Abstract] [Full Text] [PDF]
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Y. Abdallah, A. Gkatzoflia, D. Gligorievski, S. Kasseckert, G. Euler, K.-D. Schluter, M. Schafer, H.-M. Piper, and C. Schafer Insulin protects cardiomyocytes against reoxygenation-induced hypercontracture by a survival pathway targeting SR Ca2+ storage Cardiovasc Res, May 1, 2006; 70(2): 346 - 353. [Abstract] [Full Text] [PDF]
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 E. Lucchinetti, J. Feng, R. d. Silva, G. V. Tolstonog, M. C. Schaub, G. G. Schumann, and M. Zaugg Inhibition of LINE-1 expression in the heart decreases ischemic damage by activation of Akt/PKB signaling Physiol Genomics, April 13, 2006; 25(2): 314 - 324. [Abstract] [Full Text] [PDF]
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L. M. Schwartz and C. J. Lagranha Ischemic postconditioning during reperfusion activates Akt and ERK without protecting against lethal myocardial ischemia-reperfusion injury in pigs Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1011 - H1018. [Abstract] [Full Text] [PDF]
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S. P. Loukogeorgakis, A. T. Panagiotidou, D. M. Yellon, J. E. Deanfield, and R. J. MacAllister Postconditioning Protects Against Endothelial Ischemia-Reperfusion Injury in the Human Forearm Circulation, February 21, 2006; 113(7): 1015 - 1019. [Abstract] [Full Text] [PDF]
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Y. Abdallah and C. Schafer Insulin: An overall cardiovascular protector? Cardiovasc Res, January 1, 2006; 69(1): 4 - 6. [Full Text] [PDF]
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J.-C. Bopassa, R. Ferrera, O. Gateau-Roesch, E. Couture-Lepetit, and M. Ovize PI 3-kinase regulates the mitochondrial transition pore in controlled reperfusion and postconditioning Cardiovasc Res, January 1, 2006; 69(1): 178 - 185. [Abstract] [Full Text] [PDF]
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S. Lecour, N. Suleman, G. A. Deuchar, S. Somers, L. Lacerda, B. Huisamen, and L. H. Opie Pharmacological Preconditioning With Tumor Necrosis Factor-{alpha} Activates Signal Transducer and Activator of Transcription-3 at Reperfusion Without Involving Classic Prosurvival Kinases (Akt and Extracellular Signal-Regulated Kinase) Circulation, December 20, 2005; 112(25): 3911 - 3918. [Abstract] [Full Text] [PDF]
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S. Bae and L. Zhang Gender Differences in Cardioprotection against Ischemia/Reperfusion Injury in Adult Rat Hearts: Focus on Akt and Protein Kinase C Signaling J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1125 - 1135. [Abstract] [Full Text] [PDF]
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D. Obal, S. Dettwiler, C. Favoccia, H. Scharbatke, B. Preckel, and W. Schlack The Influence of Mitochondrial KATP-Channels in the Cardioprotection of Preconditioning and Postconditioning by Sevoflurane in the Rat In Vivo Anesth. Analg., November 1, 2005; 101(5): 1252 - 1260. [Abstract] [Full Text] [PDF]
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J. Vinten-Johansen, D. M. Yellon, and L. H. Opie Postconditioning: A Simple, Clinically Applicable Procedure to Improve Revascularization in Acute Myocardial Infarction Circulation, October 4, 2005; 112(14): 2085 - 2088. [Full Text] [PDF]
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P. Staat, G. Rioufol, C. Piot, Y. Cottin, T. T. Cung, I. L'Huillier, J.-F. Aupetit, E. Bonnefoy, G. Finet, X. Andre-Fouet, et al. Postconditioning the Human Heart Circulation, October 4, 2005; 112(14): 2143 - 2148. [Abstract] [Full Text] [PDF]
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D. Weihrauch, J. G. Krolikowski, M. Bienengraeber, J. R. Kersten, D. C. Warltier, and P. S. Pagel Morphine Enhances Isoflurane-Induced Postconditioning Against Myocardial Infarction: The Role of Phosphatidylinositol-3-Kinase and Opioid Receptors in Rabbits Anesth. Analg., October 1, 2005; 101(4): 942 - 949. [Abstract] [Full Text] [PDF]
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C. E. Darling, R. Jiang, M. Maynard, P. Whittaker, J. Vinten-Johansen, and K. Przyklenk Postconditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2 Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1618 - H1626. [Abstract] [Full Text] [PDF]
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E. Lucchinetti, R. da Silva, T. Pasch, M. C. Schaub, and M. Zaugg Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning Br. J. Anaesth., August 1, 2005; 95(2): 140 - 152. [Abstract] [Full Text] [PDF]
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A. Tsang, D. J. Hausenloy, and D. M. Yellon Myocardial postconditioning: reperfusion injury revisited Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H2 - H7. [Full Text] [PDF]
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