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FORUM REVIEW ARTICLE
Reperfusion Injury Salvage Kinase and Survivor Activating Factor Enhancement Prosurvival Signaling Pathways
in Ischemic Postconditioning: Two Sides of the Same Coin
Derek J. Hausenloy,1 Sandrine Lecour,2 and Derek M. Yellon1
The discovery of ischemic postconditioning (IPost) has rejuvenated the field of cardioprotection. As an inter- ventional strategy to be applied at the onset of myocardial reperfusion, the transition of IPost from a bench-side curiosity to potential clinical therapy has been impressively rapid. Its existence also confirms the existence of lethal myocardial reperfusion injury in man, suggesting that 40%–50% of the final reperfused myocardial infarct may actually be due to myocardial reperfusion injury. Intensive analysis of the signal transduction pathways underlying IPost has identified similarities with the signaling pathways underlying its preischemic counterpart, ischemic preconditioning. In this article, the reperfusion injury salvage kinase pathway and the more recently described survivor activating factor enhancement pathway, two apparently distinct signaling pathways that actually interact to convey the IPost stimulus from the cell surface to the mitochondria, where many of the prosurvival and death signals appear to converge. The elucidation of the reperfusion signaling pathways un- derlying IPost may result in the identification of novel pharmacological targets for cardioprotection. Antioxid. Redox Signal. 14, 893–907.
The recent discovery in 2003 of ischemic post-conditioning (IPost), an interventional strategy for limit- ing myocardial infarct size when applied at reperfusion (137), has revitalized the field of cardioprotection. However, the actual term IPost was first coined in 1996 to describe ven- tricular premature beat-driven intermittent reperfusion pro- tecting against reperfusion-induced ventricular fibrillation (93). And of course many years before this, the concept of modifying the process of myocardial reperfusion as a strategy for infarct-size limitation had been described in experimental studies dating back to the 1980s (99). The term IPost has highlighted the importance of intervening at the onset of myocardial reperfusion to protect the ischemic heart, a clini- cally more relevant time point for intervention in patients presenting with an acute myocardial infarction. As such, its clinical application has been rapid for both ST-elevation myocardial infarction patients undergoing primary percuta- neous coronary intervention (PCI) (120, 125) and for patients undergoing on-pump cardiac surgery (80). Its transition to the clinical setting has proven the existence of lethal myocardial
reperfusion injury in man, and these early clinical studies suggest that 40%–50% of the final reperfused infarct may be attributable to myocardial reperfusion injury (134). Of course, previous attempts to intervene at the onset of reperfusion using pharmacological agents as a strategy for protecting against myocardial reperfusion injury has been extensively investigated, and in terms of translation of the treatment strategy into clinical therapy, this has been hugely disap- pointing (11, 66, 79, 134). However, initial progress has been made with more novel approaches for preventing myocardial reperfusion injury, such as cyclosporine A (105) as a mito- chondrial permeability transit pore inhibitor and atrial natri- uretic peptide (65).
In common with its preischemic counterpart, ischemic preconditioning (IPC), intensive investigation of the signaling pathways underlying IPost have identified a number of dif- ferent signal transduction pathways conveying the cardio- protective signal from the sarcolemma to the mitochondria, some of which overlap with IPC. This article reviews two of these reperfusion signaling pathways, the reperfusion in- jury salvage kinase (RISK) pathway and the more recently described survivor activating factor enhancement (SAFE)
1The Hatter Cardiovascular Institute, University College London, London, United Kingdom. 2Hatter Cardiovascular Research Institute, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town,
ANTIOXIDANTS & REDOX SIGNALING Volume 14, Number 5, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089=ars.2010.3360
pathway, two apparently distinct signal transduction path- ways that may actually interact to convey IPost cardiopro- tection.
The RISK Pathway: Origins, Applications, and Controversies
The actual term RISK pathway was first coined by our re- search group in 2002, in a study investigating the signal transduction pathway underlying the infarct-limiting effects of urocortin administered at reperfusion (110). In that initial study, the mitogen extraregulated kinase 1=2 (MEK1=2)– extraregulated kinase 1=2 (Erk1=2) prosurvival kinase path- way was implicated as the mediator of urocortin-induced cardioprotection and the first member of the RISK pathway (110). Crucially, the administration of urocortin at the onset of myocardial reperfusion reduced infarct size and increased Erk1=2 activation over and above that achieved by reperfu- sion alone—importantly, the pharmacological inhibition of urocortin-induced Erk1=2 activation abolished the infarct- limiting effects of urocortin (110).
However, the concept of a cardioprotective antiapoptotic reperfusion pathway was actually first proposed in the late 1990s with the discovery that a variety of growth factors were capable of limiting myocardial infarct size when administered at the immediate onset of myocardial reperfusion (133). However, it must be appreciated that although these growth factors were first investigated for their potential antiapoptotic effects, it has in fact been their dramatic effects on necrosis and reductions in myocardial infarct size, which has been their most important contribution. Of course, the idea of protecting the heart by intervening at the time of reperfusion had been previously explored using a variety of approaches, some of which have been less successful, including antioxidant ther- apy, calcium channel blockers, anti-inflammatory agents, and so forth, with mixed results (134). However, initial results from more novel approaches such as cyclosporine A (105) and atrial natriuretic peptide (65) have been more promising. The novel aspect, therefore, was the possibility of recruiting pro- survival signaling pathways to protect the heart against lethal myocardial reperfusion injury. In this review article, the focus will be on the involvement of the RISK pathway in IPost signaling. For a more comprehensive account of the RISK pathway, the reader is directed to several recent reviews (17, 45, 48).
Reperfusion Signaling in IPost: The RISK Pathway
In the original description of IPost in 2003 (137), the infarct- limiting effects were attributed to the prevention of myo- cardial reperfusion injury-induced calcium overload, less oxidative stress, preserved endothelial function, attenuated apoptotic cell death, less myocardial inflammation, and ede- ma. However, the first study to implicate an actual signal transduction pathway as a mediator of IPost was by our re- search group in 2004 (127). In that study, we demonstrated that six 10-s cycles of reperfusion and ischemia applied at the immediate onset of myocardial reperfusion phosphorylated Akt, endothelial nitric oxide synthase (eNOS), and p70S6K to a greater extent than uninterrupted reperfusion in the isolated perfused rat heart (Fig. 1). Crucially, the pharmacological inhibition of phosphatidyl inositol 3 kinase (PI3K) during the
IPost protocol using either LY294002 or Wortmannin abol- ished the infarct-limiting effects of IPost and abrogated the phosphorylation of Akt, eNOS, and p70S6K (Fig. 1). Inter- estingly, the recruitment of the RISK pathway is shared with the phenomenon of IPC (43), suggesting that the RISK may be a common pathway for cardioprotection, which can be acti- vated either prior to ischemia or at the onset of myocardial reperfusion (44, 47).
The first study to implicate the MEK1=2-Erk1=2 component of the RISK pathway was that by Yang et al. (132), who demonstrated that pharmacological inhibition of MEK=12 during IPost abrogated cardioprotetion in the isolated rabbit heart. A number of experimental studies have subsequently confirmed the involvement of the RISK pathway in IPost signaling and these are briefly summarized in Table 1. There are several other protein kinases that have been implicated in IPost signaling, which could also be considered components of the RISK pathway, such as protein kinase C (PKC), protein kinase G, p38 mitogen-activated protein kinase (p38MAPK), and Jun N-terminal kinase MAPK.
The mechanism responsible for activating components of the RISK pathway in IPost is not clear, but has been attributed to cell-surface receptor binding of autacoids such as adeno- sine.
Upstream Activators of the RISK Pathway
The actual mechanism through which components of the RISK pathway are activated at the onset of myocardial re- perfusion are not clear. Most evidence supports the activation of cell-surface receptors during the IPost stimulus, which re- cruit components of the RISK pathway. It is clear from the
FIG. 1. This graph shows the infarct-to-risk ratios (%) and relative densitometries of Akt and p70S6K phosphoryla- tion during myocardial reperfusion in controls hearts and in hearts treated with ischemic postconditioning (IPost) in the presence or absence of the phosphatidyl inositol 3 ki- nase inhibitors LY294002 or Wortmannin (n> 6 per group; *p< 0.05). This figure was adapted from ref. (127).
894 HAUSENLOY ET AL.
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