© 2004 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
New directions for protecting the heart against ischaemia–reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway
The Hatter Institute and Centre for Cardiology, University College London Hospital and Medical School, Grafton Way, London WC1E 6DB, UK
* Corresponding author. Tel.: +44-207-380-9776; fax: +44-207-388-5095. d.yellon{at}ucl.ac.uk, hatter-institute{at}ucl.ac.uk
Reperfusion is a pre-requisite to salvaging viable myocardium, following an acute myocardial infarction. Reperfusion of ischaemic myocardium, however, is not without risk, as the act of reperfusion itself can paradoxically result in myocyte death: a phenomenon termed lethal reperfusion-induced injury. Therapeutic strategies that target and attenuate reperfusion-induced cell death may provide novel pharmacological agents, which can be used as an adjunct to current reperfusion therapy, to limit myocardial infarction. Recent evidence has implicated apoptotic cell death during the phase of reperfusion as an important contributor to lethal reperfusion-induced injury. Targeting anti-apoptotic mechanisms of cellular protection at the time of reperfusion may therefore offer a potential approach to attenuating reperfusion-induced cell death. In this regard, ischaemia–reperfusion has been shown to activate the anti-apoptotic pro-survival kinase signalling cascades, phosphatidylinositol-3-OH kinase (PI3K)–Akt and p42/p44 extra-cellular signal-regulated kinases (Erk 1/2), both of which have been implicated in cellular survival. Activating these pro-survival kinase cascades at the time of reperfusion has been demonstrated to confer protection against reperfusion-induced injury. We and others have shown that insulin, insulin-like growth factor-1 (IGF-1), transforming growth factor-β1 (TGF-β1), cardiotrophin-1 (CT-1), urocortin, atorvastatin and bradykinin protect the heart, by activating the PI3K–Akt and/or Erk 1/2 kinase cascades, when given at the commencement of reperfusion, following a lethal ischaemic insult. Pharmacological manipulation and up-regulation of these pro-survival kinase cascades, which we refer to as the Reperfusion Injury Salvage Kinase (RISK) pathway, as an adjunct to reperfusion may therefore protect the myocardium from lethal reperfusion-induced cell death and provide a novel strategy to salvaging viable myocardium and limiting infarct size.
KEYWORDS Reperfusion injury; Protein kinases; Growth factors
Time for primary review 27 days
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