November 23, 2003Cardiovascular Research988 citations
View Full PaperNew directions for protecting the heart against ischaemia–reperfusion injury: targeting the Reperfusion Injury Salvage Kinase (RISK)-pathway
Key Result
Pharmacological activation of the Reperfusion Injury Salvage Kinase (RISK) pathway at the time of reperfusion may protect the myocardium from lethal reperfusion-induced cell death and limit infarct size.
Structured PICO
Does targeting the Reperfusion Injury Salvage Kinase (RISK) pathway at the time of reperfusion attenuate reperfusion-induced cell death and limit infarct size in acute myocardial infarction?
P
Population
Myocardium undergoing ischemia-reperfusion following acute myocardial infarction
I
Intervention
Pharmacological agents targeting the Reperfusion Injury Salvage Kinase (RISK) pathway (e.g., insulin, IGF-1, TGF-beta1, CT-1, urocortin, atorvastatin, bradykinin) given at the commencement of reperfusion
O
Outcome
Attenuation of reperfusion-induced cell death and limitation of infarct sizesurrogate
Targeting the RISK pathway at the onset of reperfusion represents a potential adjunctive therapeutic strategy to limit myocardial infarct size.
Abstract
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-beta1 (TGF-beta1), 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.
Cite This Study
Derek J. Hausenloy (Sun,) conducted a review in Ischaemia-reperfusion injury / acute myocardial infarction. Pharmacological activation of the Reperfusion Injury Salvage Kinase (RISK) pathway was evaluated. Pharmacological activation of the Reperfusion Injury Salvage Kinase (RISK) pathway at the time of reperfusion may protect the myocardium from lethal reperfusion-induced cell death and limit infarct size.