BJA Advance Access published September 12, 2014 British Journal of Anaesthesia Page 1 of 13 doi:10.1093/bja/aeu302

Ischaemic conditioning strategies reduce ischaemia/ reperfusion-induced organ injury C. K. Pac-Soo1,2*, H. Mathew2 and D. Ma 1 1 Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Imperial College London, Chelsea and Westminster Hospital, London, UK 2 Department of Anaesthetics, Wycombe Hospital, Buckinghamshire Healthcare NHS Trust, High Wycombe, Buckinghamshire, UK

* Corresponding author. E-mail: [email protected]

† The authors review the phenomenon of attenuation of ischaemic and reperfusion injury by ischaemic pre- and post-conditioning. † They detail the known cellular and biochemical mechanisms and look forward to clinically applicable knowledge.

Summary. Reperfusion of tissues subjected to prolonged ischaemia results in ischaemic/ reperfusion injury. Fortunately, there are strategies that can be applied to attenuate this injury. These include ischaemic pre- and post-conditioning; both have been shown experimentally to reduce ischaemic/reperfusion injury by up to 75%. The molecular mechanisms of ischaemic conditioning involve the activation of surface G-protein-coupled receptors for adenosine, bradykinin, opioids, and cannabinoids. These in turn stimulate growth receptors which then trigger the activation of cytoprotective pathways resulting in a reduction in apoptosis via the mitogen-activated protein kinase/extracellular-signal regulated kinase 1/2 kinase route and a reduction in opening of mitochondrial permeability transition pores (mPTPs) via the phosphatidylinositol 3-kinase pathway. Opening of mPTPs can cause cell death. Recently, activated surface tumour necrosis factor-a receptors have been shown to also contribute to cytoprotection by activating the Janus kinase and the signal transducer and activating factor of transcription-3 pathway. Research into the mechanisms of ischaemic conditioning is still ongoing and hopefully, with the better understanding of this phenomenon, new therapeutic strategies, with possible translation into meaningful clinical trials, will be developed to reduce ischaemic/reperfusion injury. Keywords: cell signal pathway; ischaemia/reperfusion injury; mitochondria; molecular mechanism; pre- and post-conditioning

Improvements in the management of acute myocardial infarction with prompt revascularization of occluded coronary artery using thrombolysis and percutaneous coronary intervention significantly reduce complications after the ischaemic event; but paradoxically, the reperfusion of the ischaemic myocardium results in further damage to the organ. Currently, many studies are being conducted to investigate the pathophysiology of this injury with the view that understanding it will hopefully allow the development of strategies, including therapeutic options, to be used clinically to minimize the damage during this period. Research has identified, among other things, that the mitochondria, which are essential organelles for cell survival, play a significant role in triggering cell deaths during the ischaemia–reperfusion period.1 In this review, we will highlight the mechanisms of reperfusion injury, and discuss ischaemic conditioning strategies that can be used to attenuate such injury.

Ischaemia/reperfusion injury Most of the studies on ischaemia and reperfusion injury have been conducted in animal heart and brain models. Energy in cells is made available primarily as ATP; during aerobic metabolism, 38 molecules of ATP are generated for every molecule of

glucose metabolized, whereas during anaerobic metabolism, only two molecules of ATP are generated for every glucose molecule. ATPs are essential for the proper functioning of cells, including membrane transport, synthesis of chemical compounds, and mechanical work. Ischaemia of tissues severe enough will stop oxidative phosphorylation in the mitochondria leading to a rapid depletion of stored ATPs, despite the continued anaerobic glycolysis of glucose. Ischaemia of short duration can result in full recovery of the tissue after reperfusion. However, prolonged ischaemia causes irreversible necrotic tissue damage during the ischaemic period2 and after reperfusion, further injury is sustained by the latter.3 This condition is referred to as reperfusion injury, and it is associated with the generation of huge amounts of free radicals.

Mechanisms of ischaemia/reperfusion injury Free radicals and lipid peroxidation Peroxidation of lipids in mammals can be induced by enzymatic, non-enzymatic non-radical peroxidation and non-enzymatic free radical-mediated pathways.4 – 6

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Mitochondrial permeability transition pore opening The mechanisms of reperfusion injury have been studied and reviewed.17 – 20 Severe shortage of ATPs in cells during prolonged ischaemia results in failure of enzyme-dependent ion membrane transport mechanisms, leading to accumulation of intracellular calcium ions, sodium ions, and the generation of lactate during glycolysis results in a decrease in intracellular pH.17 – 21 The increase in cellular ions causes an increase in osmotic pressure resulting in swelling and rupture of cells; an increase in cellular calcium ions produces cell death by necrosis, apoptosis, and autophagy.17 – 21 During severe ischaemia, most ATPs are used up and converted into ADPs; however, the build up of cellular ADP is not stored but is degraded into adenosine monophosphate (AMP), the latter is further degraded into adenosine, inosine, and hypoxanthine.9 20 22 Hypoxanthine is oxidized into urate by xanthine oxidase system and during this process, molecular oxygen is reduced to superoxide anions.9 20 22 Xanthine dehydrogenase –xanthine oxidase

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enzyme system is present in all cells and in normal conditions exists predominantly as xanthine dehydrogenase, but during severe ischaemia, it is preferentially converted into xanthine oxidase.20 23 Free radicals are also generated by the respiratory complex enzymes in mitochondria. During the ischaemic period, because of cellular acidosis and reduced oxygen tension, all enzymatic activities are reduced including xanthine oxidase and also because of the reduced level of cellular oxygen, only a small amount of free radicals is produced. During reperfusion, the increase in cellular oxygen levels and normalization of cellular pH result in the return of normal enzymatic activities and these together with the excessive amount of hypoxanthine present lead to the generation of huge amounts of superoxide anions and subsequent peroxidation of lipids.9 20 22 Furthermore, the increased level of cellular calcium ions, the return of normal cellular pH, and the huge increase in free radicals generated during reperfusion all together act upon and produce a prolonged opening of mitochondrial permeability transition pores (mPTPs) resulting in the release of mitochondrial contents into the cytosol and also the collapse of the mitochondrial potential.18 24 – 27 The opening of mPTPs is believed to be the final common pathway leading to cell death by necrosis and apoptosis during the reperfusion phase after a prolonged period of ischaemia;28 29 inhibition of cyclophilin, a peptidyl propyl cis –trans isomerase enzyme present in the mitochondrial matrix, by cyclosporine A, prevents the opening of mPTPs and reduces significantly the extent of cellular injury.30 The released cytochrome C from the mitochondria contributes significantly to cellular apoptosis during the reperfusion period.27 The large amounts of ROS and RNS species, the lipidderived free radicals together with their end products, mainly aldehydes, which are generated during reperfusion, contribute further to direct tissue injury.31 – 37 Free radicals cause fragmentation and modification of proteins,33 resulting in an increase in the susceptibility of the latter to proteolytic degradation.37 The aldehyde products of lipid peroxidation covalently attach themselves to proteins and DNAs resulting in alterations in their original functions.31 32 35 36 For example, malonaldehyde, 4-hydroxy-2(E)-hexenal, 4-hydroxynonenal, acrolein, derived from lipid hydroperoxides, activate caspase pathways, and induce apoptosis; they also increase the susceptibility of proteins to proteosome degradation, cause disruption of cell signalling, they inhibit protein functions by altering their tertiary structures, aldehydes can damage DNAs,14 35 36 38 modify heat shock protein HSP72, and impair its cytoprotective functions.14 38 39

Ischaemic conditioning The release of massive amounts of free radicals, lipid hydroperoxides, and their derived products during reperfusion, after a prolonged period of ischaemia, causes cellular damage and cell death. However, their release in smaller amounts after limited, less severe ischaemic and hypoxic insults can confer some degree of protection to the cells to subsequent much

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Free radicals are molecules or atoms with unpaired electrons in their outer shell and they are highly reactive. Free radicals produced from oxygen are called reactive oxygen species (ROS) and include superoxide anion (O2 ) and hydroxyl radical (OH ), and those derived from the reaction of oxygen with nitrogen are called reactive nitrogen species (RNS) and they include nitric oxide (NO ) and peroxynitrite (ONOO ). Free radicals are produced by mammalian cells, superoxide production is catalysed by NAP(P)H oxidase and xanthine oxidase enzymes, the latter being important in the production of ROS during oxidative reperfusion injury.7 – 9 O2 is also produced in mitochondria by a reduction in oxygen in respiratory complexes I and III.10 11 Superoxide produced is then converted, by superoxide dismutase (SOD), into the non-radical hydrogen peroxide which can react with excess superoxide in the presence of ferrous or cuprous ions to produce the highly reactive hydroxyl radical (OH ).12 Nitric oxide is produced by endothelial, neuronal, and inducible nitric oxide synthase enzymes. The hydroxyl radical is an extremely strong oxidant and can abstract allylic hydrogen, add hydroxylate, or accept electrons. The hydroxyl radical is an important initiator of peroxidation of membrane lipids, phospholipids, and cholesterol; it abstracts methylene hydrogen atoms from polyunsaturated fatty acids present in membranes to produce lipid-derived free radicals including dienes, lipid hydroperoxide radicals (LOO ), and lipid hydroperoxides (LOOH).13 14 These products set a chain reaction triggering further free radical-mediated peroxidation of polyunsaturated membrane lipids, generating new hydroxyperoxide products. In mammals, because of the diversity of polyunsaturated fatty acids in membranes, radical-mediated oxidation of membranes generate between 120 and 150 kinds of hydroperoxides.15 ROS and RNS free radicals, because they are unstable, have short half-lives, can only produce their effects locally. However, lipid hydroperoxides and their breakdown products, including aldehydes, which have longer half-lives, can move within and between cells and exert their effects beyond their sites of origin.13 14 16

Pre- and post-conditioning

Molecular mechanisms of ischaemic preconditioning Preconditioning results in an early phase and a late phase of protection to a subsequent severe prolonged ischaemic insult. The early phase starts immediately after the conditioning stimuli and lasts up to 2 h, and the late phase starts 12–24 h after the stimuli and lasts up to a few days. The generation of small

amounts of free radicals during the preconditioning period is essential for both early and late phase of protection,52 60 but unlike the early phase, the late phase is associated with the expression of several prosurvival genes, including glucose transporter-1 and -4 (GLUT-1 and GLUT-4), heat shock protein 70, and vascular endothelial growth factor, triggered by the increased levels of hypoxia-inducing factor 1a (HIF-1a) after the ischaemic preconditioning stimuli.61 The role of HIF-1a in cell survival during ischaemia – reperfusion has been reviewed.62 HIF-1a is an important transcription factor mediating cellular responses to hypoxia. In normoxic conditions, HIF-1a is hydroxylated by prolyl hydrolases (PHDs); this process facilitates its binding to von Hippel –Lindau protein leading to its subsequent removal by polyubiquitylation and proteasomal degradation.63 In hypoxic conditions, PHD activity is inhibited allowing HIF-1a levels to increase and cause the expression of hypoxia response genes in the cells.63 Natarajan and colleagues64 showed that silencing the PHD gene in mice 24 h before ischaemia resulted in a reduction in PHD enzyme levels and a time-dependent increase in cellular HIF-1a levels. This produced a reduction in the area of myocardium infarction and better recovery of left ventricular function after reperfusion after a period of myocardial ischaemia.64 The role of HIF-1a in delayed preconditioning is also confirmed by Adluri and colleagues,65 in a study in mice, where they showed that transgenic PHD knocked out mice (PDH-12/2 KO) had higher levels of HIF-1a, reduced area of myocardial infarction, reduced myocardial apoptosis, increased b-catenin, endothelial nitric oxide synthase enzyme activity, and antiapoptotic BcL-2 levels compared with the wild-type control mice after an ischaemia/ reperfusion protocol. During ischaemic preconditioning, in the early phase, ischaemic tissues release agonists, including adenosine, bradykinin, and opioids; these activate their respective G-protein-coupled receptors (GPCRs), which eventually phosphorylate and activate matrix metalloproteinase.66 – 72 These in turn phosphorylate and activate growth factor receptors, for example, epidermal growth factor receptors (EGFR) and signalling cascades culminating in cytoprotection.66 – 73 It is well established that m-, k-, and d-opioid agonists, when bound to pertussis toxin-sensitive heterotrimeric G protein receptors, mediate their cell signalling mechanisms by phosphorylating and stimulating the extracellular-signal-regulated protein kinases ERK 1 and 2.74 In the context of preconditioning, opioids also mediate their cytoprotective effect via this pathway. Ma and colleagues69 demonstrated, in cultured rat cortical neurones, that preconditioning produced an upregulation and activation of d-opioid GPCRs resulting in an increase in phosphorylation of ERK followed by downstream activation of PKC. The latter induced an increase in levels of BcL-2 and a decrease in the release of cytochrome C, the net effect was a decrease in cell death during reperfusion after a period of severe hypoxia.69 The other released autacoids, adenosine and bradykinins, have also been shown to mediate their preconditioning effects via the ERK pathway.75 – 77 These autacoids, acting via the GPCRs, growth receptors, and MEK/ERK1/2,

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more severe insult,7 40 – 43 and contribute to the condition referred to as preconditioning. Preconditioning was first described by Murry and colleagues44 in 1986, in dogs, where the team showed that four cycles of 5 min of ischaemia by coronary occlusion each separated by 5 min of reperfusion before a 40 min of ischaemia produced a 75% reduction in the size of myocardial infarction after reperfusion compared with non-preconditioned hearts. Subsequent to the discovery of preconditioning, Zhao and colleagues45 showed, in a heart model in dogs, that after a 60 min period of ischaemia by coronary occlusion, three cycles of 30 s of reperfusion started immediately after reperfusion followed each by 30 s of occlusion produced a 40% reduction in infarct size after a 3 h reperfusion period compared with control which did not undergo the above protocol; this was called post-conditioning. In their model, the amount of protection provided by post-conditioning was similar to a preconditioning protocol.45 The timing of post-conditioning is crucial as delaying the procedure by a minute after reperfusion is enough to result in complete loss of its protective effects.46 Post-conditioning is associated with a significant reduction in the release of free radicals during the early period of reperfusion and this is believed to contribute to the reduction in cellular injury during that phase.46 Both pre- and post-conditioning can confer some clinical benefits, for example, during elective cardiac surgery and during coronary angioplasty after acute myocardial infarction.47 – 51 Although some of the pathways of cytoprotection have been defined, the definite mechanisms of pre- and postconditioning still remain unknown. However, the production of small amounts of free radicals is essential for their effects,45 52 – 54 and furthermore, pre- and post-conditioning confer cellular protection by activating several signalling pathways, which culminate in the inhibition of the opening of mPTPs during reperfusion.29 55 Membrane receptors for ligands including adenosine, bradykinin, opioids, cannabinoids, tumour necrosis factor (TNFa), and the ATP-sensitive K+ channels (KATP channels), protein kinase C (PKC), extracellular receptor protein kinase mitogen-activated protein kinase p42/44, P38 mitogen-activated protein kinase (p38 MAPK), janus kinase (JAK), signal transducer and activating factor of transcription-3 (STAT-3), glycogen synthase kinase 3b (GSK-3b), the Reperfusion Injury Salvage Kinases (RISK) pathway including extracellular-signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase/AKT (PI3-K/AKT) have been implicated in ischaemic conditioning. Recently, the Survivor Activating factor Enhancement (SAFE) kinase pathway has also been linked to these conditions.43 56 – 59

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the opening of mPTP.94 It has also been suggested that the mammalian target of rapamycin (mTOR) is the downstream pathway of GSK-3b mediating ischaemic and pharmacological preconditioning.54 mTOR is a member of the PI3-K kinase enzymes and one of its known functions is to control proteins which modulate the translation of mRNAs.96 The PI3-K/AKT/PKB pathway not only mediates the reduction in ischaemia/reperfusion injury, after preconditioning, by inhibiting GSK-3b-mediated opening of mPTPs but also by inhibiting apoptosis mediated by the Bcl-2 protein-induced mitochondrial outer membrane permeabilization.97 The effect of PI3-K/AKT/PKB on the Bcl-2 family of proteins can be explained by the cross-talk between PI3-K/AKT/PKB and MEK/ERK1/2 pathways.88 Kunuthur and colleagues88 showed that, after ischaemic preconditioning, phosphorylation and activation of ERK 1/2 pathway occurred in the wild-type AKT1+/+ mice, but this was significantly reduced in the Akt12/2 mice.

Molecular mechanisms of ischaemic post-conditioning Prosurvival kinase pathways PI3-K/AKT/PKB and ERK1/2 which mediate preconditioning (Fig. 1) are also important in postconditioning.98 – 101 In a study in minipigs, post-conditioning produced an increase in phosphorylation of AKT and GSK-3b and a reduction in myocardial injury 24 h after reperfusion and this effect was abolished after inhibition of PI3-K with wortmannin.100 Sivaraman and colleagues,102 in a study of human atrial tissues harvested during coronary artery bypass graft (CABG) surgery, showed that the improvement in cardiac contractile function produced by post-conditioning was mediated via the PI3-K and ERK1/2 pathways as it was blocked and significantly reduced by PI3-K inhibitor LY294002 and ERK1/2 inhibitor UO126, respectively. Unlike the other studies, Darling and colleagues103 were only able to demonstrate the involvement of ERK1/2 pathway in post-conditioning, in rabbit hearts. They showed a reduction in the size of myocardial injury in the postconditioned group and this was associated with an increase in phospho ERK1/2, but no change in phospho AKT;103 the protective effect was blocked by inhibition of ERK1/2 with PD-98059 but not by LY-294002, a PI3-K blocker.103 The cell signalling pathways mentioned above are illustrated in Figure 1. While the release of autacoids and activation of their respective surface receptors during ischaemic preconditioning explains the initiating mechanism of preconditioning, postconditioning is more difficult to explain. Several investigators have postulated that adenosine released in huge amounts immediately during the early phase of reperfusion, after a prolonged ischaemic period, may trigger post-conditioning by acting on adenosine receptors.67 104 105 For example, Eldaif and colleagues104 showed that, in rats in which the right kidney was removed and the left renal artery and vein were occluded for 40 min and followed by 24 h of reperfusion, a postconditioning protocol reduced tubular cell damage and apoptosis and this renoprotective effect was lost when an adenosine receptor blocker 8-p-(sulfophenyl) thoephylline (8-SPT) was administered before post-conditioning. Zhan and

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modulate the cellular apoptotic process by increasing and decreasing the expression of antiapoptotic and proapoptotic BcL-2 family of proteins, respectively, shifting the balance towards a reduction in cell apoptosis much like in cancer cells.69 75 78 79 The increase in expression of antiapoptotic Bcl-2 proteins can result from an increase in transcription or translation of mRNAs.78 79 The important role the Bcl-2 family of proteins plays in apoptosis came to light after studies on cancer pathways. These proteins control the permeabilization of the mitochondrial outer membrane; for example, activation of cytosolic Bcl-2 protein bid (t-bid) results in its translocation to the outer mitochondrial membrane where it anchors proapoptotic Bax allowing the latter to polymerize and form membrane pores.80 – 82 The antiapoptotic Bcl-2 proteins, for example, Bcl-2, Bcl-XL, and Mcl-1, by binding to the activators the BH-3 only proteins, for example, t-bid and Bim, prevent the binding and activation of the proapoptotic Bcl-2 proteins.80 – 82 MEK/ERK1/2 is not the only pathway mediating preconditioning. Research have demonstrated that the autacoids released during preconditioning acting on their respective GPCRs also mediate their effect via the phosphatidylinositol 3-kinase (PI3-K) pathway.75 76 83 They showed that inhibition of PI3-K with wortmannin resulted in the reduction in the protective effect of preconditioning.75 76 It is well known that one of the downstream targets of PI3-K is the oncogene product of the retrovirus AKT8, AKT/protein kinase B (PKB), a serine/threonine kinase.84 85 Phosphorylation of PI3-K, after, for example, activation of growth factor receptors, produce phosphoinositides which bind to pleckstrin homology (PH) domain of AKT/ PKB and phosphoinisitide-dependent protein kinase (PDK) leading to the translocation of AKT/PKB to the plasma membrane where they are phosphorylated and activated by PDK.85 86 This PI3-K/AKT/PKB pathway is also involved in preconditioning.83 87 Kunuthur and colleagues88 showed, in a transgenic mice model, that ischaemic preconditioning produced phosphorylation and activation of Akt1 and Akt2 receptors and this resulted in the inhibition of downstream GSK-3b, similar to the inhibition of this enzyme produced by stimulation of insulin receptors.89 Human d-opioid receptors mediate the inhibition of GSK-3b activity via a complex signalling pathway involving Src-dependent transphosphorylation of plateletderived growth factor receptor b, insulin growth factor-1 receptor, PI3-Ka activation of AKT, and AMP-activated protein kinase.90 This pathway is also involved in cytoprotection after preconditioning.83 91 Indeed, prosurvival kinase pathways have been shown to converge onto and inhibit GSK-3b by phosphorylating the N-terminal serine residue (ser9).92 – 94 GSK-3b is involved in the regulation of many cell signalling events; it is active in the basal state and it phosphorylates serine or threonine amino acids on substrates and its effects are terminated by phosphatases.95 GSK-3b is present in the mitochondria and it is associated with components of the mPTP.94 It is the convergence point of the cytoprotective pathways and it controls the opening of the mPTP.94 Inhibition of GSK-3b by upstream cytoprotective signalling pathways involving PI3-K/ AKT/PKB probably results in the release of inhibition of downstream signalling pathways, allowing the latter to prevent

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Fig 1 Cell signalling reperfusion injury salvage kinase (RISK) pathways of ischaemic conditioning. MEK/ERK 1/2, mitogen-activated protein kinase/ extracellular signal-regular kinase 1/2; PI3-K, phosphatidylinositol 3-kinase; PDK, phosphoinositide-dependent protein kinase; AKT/PKB, protein kinase B; PKG, protein kinase G; PKC-1, protein kinase C-1; GSK-3b, glycogen synthase kinase-3b; mTOR, mammalian target of rapamycin; mKATP, mitochondrial ATP-dependent potassium channel; ROS, reactive oxygen species.

colleagues showed,105 in mice hearts, that adenosine A1 receptor stimulation protected the myocardium during the reperfusion phase of ischaemia/reperfusion only when A2A and A2B receptor subtypes were fully functional as A1 stimulation failed to condition the heart in A2A and A2B knocked out mice and when it was administered together with A2A and A2B antagonists during the reperfusion period. In another study in mice hearts, Methner and colleagues67 also confirmed the importance of A2A and A2B adenosine receptor subtypes in post-conditioning, and furthermore, they postulated that the two receptors must be working in concert to provide the cytoprotection because this was lost when one of the receptors was blocked or when only one agonist to the two receptors was administered to transgenic CD732/2 mice, which could not produce adenosine. The involvement of A2A receptor subtypes in post-conditioning was also confirmed by Kin and colleagues106 in their experiment in rat hearts, and in addition, they found that the A3 receptor subtypes were also required. These authors went on further to postulate that postconditioning produced cytoprotection by retaining adenosine in the coronary circulation for longer in the early minutes after reperfusion, allowing the agonist enough time to activate the adenosine receptors and trigger the salvage kinase pathways by showing that the levels of adenosine in the coronary venous system were higher in the post-conditioning groups than the control groups 2 and 3 min after reperfusion.106

Most studies on pre- and post-conditioning have been performed on rabbits, mice, pigs, and dogs. Yang and colleagues107 were the first to have conducted conditioning studies in non-human primates, Cynomolus monkeys. They showed that an ischaemic preconditioning protocol of 10 min of coronary occlusion followed by 10 min of reperfusion performed twice before 90 min of coronary occlusion followed by 4 h of reperfusion prevented myocardial infarction (infarct to risk zone ratio of about 2%) compared with control which showed an infarct to risk zone ratio of about 44%. Administration of wortmannin at the end of preconditioning before reperfusion did not abolish but reduced the protection provided by preconditioning producing an infarct to risk zone ratio of about 17%.107 This showed that the beneficial effect of ischaemic preconditioning occurred not only at reperfusion as demonstrated by Hausenloy and colleagues87 but also during the ischaemic period. Yang and colleagues107 also showed that post-conditioning consisting of six cycles of 30 s of coronary occlusion followed by 30 s of perfusion started immediately during the reperfusion phase was not as protective as the preconditioning protocol as this produced an infarct to risk zone ratio of about 28%. This is in contrast to the studies in other species where post-conditioning was found to be as protective as preconditioning. It might mean that post-conditioning strategies in humans might not be as beneficial as we thought.

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Fig 2 Cell signalling survivor activating factor enhancement (SAFE) pathways of ischaemic conditioning. TNFa, tumour necrosis factor-a; JAK, janus kinase; STAT-3, signal transducer and activating factor of transcription-3.

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possible cross-talk between these two cytoprotective pathways.59 This has been highlighted in several studies, for example, Goodman and colleagues117 showed, in an isolated perfused mice heart model, that JAK-STAT (SAFE) and RISK pathways are both activated during post-conditioning; furthermore, they showed that JAK-STAT might be working parallel to or upstream of RISK pathway and that the RISK pathway must be functional for JAK-STAT pathway to work fully.

Common mechanisms of pre- and post-conditioning (mitochondrial ATP-dependent potassium channels) We described above that ischaemic pre- and post-conditioning resulted in the release of autacoids including adenosine, opioids, and bradykinin and that these activated their corresponding GPCRs and mediated the conditioning effects. Ischaemic pre- and post-conditioning stimuli-induced cytoprotection also caused the opening of mitochondrial ATP-dependent potassium (mKATP) channels,120 – 123 and direct opening of mKATP channels using diazoxide before ischaemic/reperfusion produced cytoprotection.120 124 Therefore, it is logical to postulate that there may be a link between activation of surface GPCRs during the conditioning stimuli, opening of mKATP channels, and cytoprotection. Indeed, the results of many studies support this theory57 66 121 125 – 128 (Fig. 1). For example, Cao and colleagues66 showed in rabbit heart that opioid receptorinduced cytoprotection during preconditioning was blocked by mKATP channel blocker 5-hydroxydecanoate, Penna and colleagues57 showed in rat heart that bradykinin-induced cytoprotection during post-conditioning was blocked by 5-hydroxydecanoate, and Reshef and colleagues128 showed in cultured myocardial cells that adenosine receptor-mediated cytoprotection was blocked by non-selective ATP-dependent potassium channel blocker glibenclamide. The questions arising from this are how do pre- and post-conditioning cause opening of mKATP channels and how does opening of mKATP channels produce cytoprotection? Opening of mKATP channels is mediated by PKC. Uchiyama and colleagues120 showed, in a rat heart model, that ischaemic preconditioning caused the activation of PKC and the opening of mKATP channels, and furthermore, they showed that the opening of mKATP channels was mediated by activated PKC because it was blocked by PKC inhibitors Ro318425 and celerythrine. Miura and colleagues129 showed, in a rabbit heart model, that activated adenosine A1 GPCRs produced the reduction in myocardial ischaemic/reperfusion injury by an activated PKC-mediated phosphorylation and opening of mKATP channels. The opening of mKATP channels by activated PKC during pre- and post-conditioning has also been reported in many other studies, which in addition showed that it is the PKC-1 isoform which is responsible for this.126 129 – 132 The activated PKC-1 phosphorylates a specific component of the mKATP channels, the Kir6.2 moiety,126 133 and furthermore, postconditioning up-regulates the Kir family of mKATP channels.134 Kirs are known pore-forming proteins and when the kir6.2

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Yellon and Baxter,108 in their paper in 1999, were the first to propose a prosurvival kinase pathway involving various growth factors acting on cell surface receptors, the PI3 K/AKT and the ERK/MAP kinase p42/44 which reduced cell death by apoptosis during reperfusion after a period of ischaemia by inhibiting proapoptotic and enhancing antiapoptotic proteins. Subsequently, they extended the role of the prosalvage kinase pathway AKT and ERK to also include the protection provided by pre- and post-conditioning from cell death by necrosis during the reperfusion period and introduced the concept of a Reperfusion Injury Salvage Kinase (RISK) pathway.109 Myocardial cells express membrane TNFa receptors and they can also produce TNFa cytokines; both TNFa and TNFa receptors are up-regulated in myocardial cells after ischaemic stimuli.110 111 Experimental studies have shown that TNFa can have both deleterious and protective effects on cardiac cells during reperfusion, but unlike the other membrane agonists involved in pre- and post-conditioning, TNFa cytoprotection is not mediated via the RISK pathway.112 113 Instead, it is mediated by activating the janus kinase (JAK) and the signal transducer and activating factor of transcription 3 (STAT-3) kinases in the newly described cytoprotective Survivor Activating Factor Enhancement (SAFE) pathway114 – 116 (Fig. 2). The TNFa receptor involved in SAFE pathway can be activated by cytokines and growth factors. Like the RISK pathway, the SAFE pathway is also involved in both pre- and postconditioning.115 117 – 119 There has been speculation about a

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Clinical evidence for ischaemic conditioning The few small clinical studies evaluating classical pre- and post-conditioning strategies overall have shown small clinical benefits.142 – 145 For example, Jebeli and colleagues142 showed, in a study of 40 patients undergoing elective CABG surgery, that those who followed an ischaemic preconditioning protocol before cross-clamping of the aorta for CABG surgery had better left ventricular ejection fraction, required less inotropic support after operation than patients in the control group. Jenkins and colleagues143 on the other hand, in a study of 33 patients undergoing elective CABG surgery, showed that preconditioning on bypass before aortic crossclamping significantly reduced myocardial injury as measured by serum levels of troponin T 72 h after surgery. However, this did not result in significant differences in changes in ECG after operation between the preconditioning and control

groups.143 It could be argued that, in these studies, the ischaemic conditioning strategies were applied to a population where the area at risk during the ischaemic insult was small with relatively fewer cells at risk of reperfusion injury. Ischaemic conditioning strategies will be more beneficial clinically in conditions where much greater tissues are at risk during the ischaemic period. Xue and colleagues145 demonstrated that postconditioning conferred benefits to patients with acute myocardial infarction. They showed, in a study of 43 patients admitted with acute myocardial infarction, that a post-conditioning protocol, started within 1 min after reflow after angioplasty, improved the resolution of elevated ST segment on ECG, improved left ventricular function, and reduced myocardial infarction size.145 In a pilot study of 43 patients admitted with ST-elevation myocardial infarction, Garcia and colleagues144 showed that a post-conditioning protocol started immediately after angioplasty and stent insertion reduced the size of myocardial infarction, peak serum creatine phosphokinase, and its MB isoform. Furthermore, they showed that these were associated with an improvement in left ventricular function which persisted up to a mean follow-up of 3.4 yr after the myocardial infarction.144 In a prospective randomized controlled study performed in 50 patients admitted within 12 h of an ST-segment elevated myocardial infarction (STEMI), Thuny and colleagues146 showed that a post-conditioning protocol started within 1 min of reflow of the obstructed coronary artery reduced the area of myocardial infarction and area of oedema measured by magnetic resonance imaging and also reduced the peak plasma creatinine kinase level. In contrast, Tarantini and colleagues147 showed, in a study of 78 patients out of 453 who were admitted within 6 h of STEMI, that a postconditioning protocol started within 1 min of reflow after stent insertion failed to have any cardioprotective effect and worse it was associated with a trend towards an increase in microvascular obstruction and major adverse cardiac events in the treated group. In this study, there were more patients with diabetes in the ischaemic post-conditioning group, but this did not influence the trend towards an increase in the size of infarction and adverse cardiac events in that group according to the authors as it was taken into consideration when the data were analysed.147 Furthermore, Tarantini and colleagues147 pointed out that they administered abciximab i.v. to all their patients before percutaneous coronary intervention, unlike in the other studies where the drug was given at the discretion of the operator or its use was not specified. The authors wondered whether this might have influenced the result of their study.147

Remote ischaemic conditioning and its clinical application There are obvious limitations to the application of classical ischaemic conditioning strategies in clinical practice; for example, it is impossible to institute ischaemic postconditioning after an ischaemic cerebrovascular accident not least because it is difficult to control the timing of reperfusion of the brain tissues after thrombolysis. Remote ischaemic

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components of mKATP channels are phosphorylated, they form pores and increase K+ conductance.126 Pre- and post-conditioning activate PKC-1 by several potential pathways.57 135 – 137 GPCR receptor stimulation can activate phospholipase A and D enzymes resulting in the generation of diacylglycerol from inositol 1,4,5-trisphosphate, which then activates PKC. Conditioning stimuli induce activation of GPCRs which, via the salvage kinase pathways, phosphorylate and activate protein kinase G.57 131 135 138 For example, Oldenburg and colleagues138 showed, in a rabbit heart and cell culture models, that bradykinin produced cytoprotection by activating PKG via PKB/AKT pathway, and furthermore, they showed that PKG was upstream of mKATP channels. Penna and colleagues57 showed, in a rat heart model, that post-conditioning activated bradykinin B2 receptors which triggered the activation of the downstream salvage kinase pathways and mediated cytoprotection via activation of PKG as this effect was blocked by the separate administration of antagonists to BK and PKG. The activated PKG then phosphorylates and activates PKC-1.131 135 Garlid and colleagues130 suggested that after conditioning stimuli, the interactions between membrane GPCRs, salvage kinase pathways, and mKATP channels occur in an enclosed compartment.135 They postulated, following results of their studies on pre- and post-conditioning stimuli, that the activated GPCRs, bradykinin receptors, would join the signalling molecules of the salvage kinase pathways in caveolae, which they called GPCR signalosomes. The whole complex would travel to the outer mitochondrial membrane where the terminal-activated kinase PKG would activate PKC-1, the latter would then phosphorylate and cause opening of the mKATP channels.130 135 The opening of mKATP channels, by conditioning stimuli or by pharmacological agents, results in an influx of potassium ions into the mitochondrial matrix.130 131 136 139 – 141 This causes an increase in the matrix volume136 139 and matrix pH,139 140 both contributing to the increase in the production of ROS.136 139 140 The mKATP channel-dependent ROS produced then phosphorylate and activate the mitochondrial PKC-1,131 136 the later inducing cytoprotection by inhibiting the opening of mPTP.131

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of 5 min ischaemia followed by 5 min reperfusion of the left upper limb before elective CABG produced a significant reduction in perioperative myocardial injury, the primary endpoint of the study. Furthermore, they showed that this was associated with a significant reduction in all-cause mortality up to 1 yr after surgery.151 Patients undergoing vascular surgery, cardiac surgery, and coronary interventions are at significant risk of acute kidney injury and it has been suggested that remote ischaemic preconditioning may protect against this. However, only a few small studies have been published so far. In a meta-analysis study including 10 published studies of patients undergoing cardiac surgery, vascular surgery, and percutaneous coronary intervention with a total of 464 patients, Li and colleagues,162 using the random effect model statistics, failed to show any beneficial effects of remote ischaemic preconditioning on postoperative acute kidney injury but showed a small beneficial effect when the fixed effect model was applied. This clearly warrants further large clinical studies. In a study of 242 patients undergoing elective percutaneous coronary stent insertion, remote ischaemic preconditioning of an upper limb significantly reduced myocardial injury with a lower serum cardiac troponin I 24 h after the procedure in the treatment group, the primary endpoint of the study, and also reduced the risk of cardiovascular and cerebral events up to 6 months after the intervention, the second endpoint of that study.163 In a follow-up study of these patients, Davies and colleagues164 showed that the beneficial effects of remote ischaemic preconditioning persisted up to 6 yr after the procedure with lower cardiovascular and cerebral events in the treatment group. Unlike the studies described above, Lavi and colleagues,165 in a study of 360 patients, failed to show that remote post-conditioning applied at the time of atherectomy during elective percutaneous coronary interventions reduced periprocedural myocardial injury. Such a difference may be attributed to remote preconditioning being more effective than remote post-conditioning and it may also be that remote post-conditioning is better when it is applied at the onset of reperfusion immediately after stent insertion.144 146

Summary Reperfusion after a prolonged period of ischaemia produces ischaemia/reperfusion injury to organs by necrosis, apoptosis, and autophagy. These are triggered by an increase in cellular ions, free radicals, and the products of lipid peroxidation. The cells have adaptive mechanisms which can attenuate the ischaemia/reperfusion injury. These are activated by short periods of ischaemia followed by reperfusion before or immediately after the prolonged severe ischaemia. The molecular mechanisms of pre- and post-conditioning strategies are being discovered and involve signalling pathways including surface GPCRs, matrix metalloproteinases, growth receptors, extracellular receptor kinase MEK/ERK1/2 and the apoptotic pathway, the PI3-K AKT/PKB and mPTPs, the mKATP channels and PKC, and TNFa, TNFa receptors, and the JAK-STAT pathway. Although pre- and post-conditioning protocols

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conditioning, a modified form of ischaemic conditioning, shows promise and it is much easier to apply clinically.148 – 152 It was first described by Przyklenk and colleagues153 in an in vivo canine heart model where the authors showed that four cycles of 5 min of circumflex branch artery occlusion followed by 5 min of reperfusion produced about 35% reduction in infarct size in the territory of the left anterior descending artery after 1 h of occlusion of the latter. The mechanism of remote ischaemic conditioning remains largely unknown, and it is speculated that it may be mediated via neural pathways and humoral factors released by ischaemia–reperfusioned tissues and that it shares some of the molecular pathways of the conventional ischaemic conditioning.154 – 158 Loukogeorgakis and colleagues157 showed, in 19 adult human volunteers, that remote ischaemic pre- and postconditioning by intermittently inflating and deflating a cuff applied to an upper limb protects the vascular endothelium of the brachial artery of the contralateral limb from ischaemia– reperfusion injury and that this was mediated via KATP channels as it was blocked by glibenclamide. This concept was first applied clinically for specific organ protection at risk of ischaemic– reperfusion injury in a study of children undergoing repair of congenital cardiac defects.159 It showed that remote ischaemic preconditioning by four 5 min cycles of inflation at least 15 mm Hg above systolic arterial pressure and deflation of an arterial pressure cuff applied to a lower limb significantly reduced myocardial injury measured as serum troponin I levels and also reduced postoperative inotropic requirements.159 Remote ischaemic conditioning has subsequently been confirmed in other studies in the adult population. For example, Hausenloy and colleagues,160 in a study of 57 patients undergoing elective CABG, showed that remote ischaemic preconditioning consisting of three 5 min cycles of inflation to 200 mm Hg and deflation of a cuff applied on an upper limb significantly reduced serum cardiac troponin T up to 48 h after surgery. D’ascenzo and colleagues152 performed a meta-analysis of published studies up to year 2012 evaluating the cardioprotective effects of remote ischaemic preconditioning in patients undergoing elective CABG. They included nine studies with a total of 704 patients and showed that three cycles of 5 min ischaemia followed by 5 min of reperfusion of an upper limb before CABG significantly reduced cardiac troponin I and T levels after operation, an indicator of myocardial injury.152 In another meta-analysis study of 23 studies published up to year 2012 with a total of 954 treated and 924 controlled patients undergoing cardiac surgery, vascular surgery, and percutaneous coronary interventions, Brevoord and colleagues161 showed that although remote ischaemic conditioning significantly reduced myocardial injury, it failed to reduce mortality associated with ischaemic events. This may be due to the heterogeneous populations and procedures studied. The effect of remote ischaemic conditioning on mortality would be better evaluated in a homogenous population undergoing similar procedures in an adequately powered large randomized study. Indeed more recently, Thielmann and colleagues,151 in a large single-centre study of 329 patients, showed that remote ischaemic preconditioning consisting of three cycles

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significantly attenuate ischaemia/reperfusion injury in experimental models, they have not been translated fully into clinical use. One of the main problems with ischaemic conditioning strategies is that they are difficult to implement effectively in clinical practice. Remote conditioning is much easier to apply clinically, and furthermore, its clinical application shows promise. However, further studies are need to increase our understanding of the mechanism of remote conditioning.

Authors’ contributions C.K.P.-S. and D.M. generated the idea and all authors contributed to the writing up of the review.

D.M. is a board member of British Journal of Anaesthesia.

References 1 2

3 4

5

6 7 8 9 10 11 12

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16 17

Ong SB, Gustafsson AB. New roles for mitochondria in cell death in the reperfused myocardium. Cardiovasc Res 2012; 94: 190– 6 Jennings RB, Reimer KA, Jones RN, Peyton RB. High energy phosphates, anaerobic glycolysis and irreversibility in ischemia. Adv Exp Med Biol 1983; 161: 403–19 Hearse DJ. Reperfusion of the ischemic myocardium. J Mol Cell Cardiol 1977; 9: 605– 16 Niki E, Yoshida Y, Saito Y, Noguchi N. Lipid peroxidation: mechanisms, inhibition, and biological effects. Biochem Biophys Res Commun 2005; 338: 668– 76 Basu S. Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients. Toxicology 2003; 189: 113– 27 Porter NA, Caldwell SE, Mills KA. Mechanisms of free radical oxidation of unsaturated lipids. Lipids 1995; 30: 277–90 Bae YS, Oh H, Rhee SG, Yoo YD. Regulation of reactive oxygen species generation in cell signaling. Mol Cells 2011; 32: 491–509 Droge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82: 47 –95 Granger DN. Role of xanthine oxidase and granulocytes in ischemia –reperfusion injury. Am J Physiol 1988; 255(6 Pt 2): H1269– 75 Divakaruni AS, Brand MD. The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda) 2011; 26: 192– 205 Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009; 417: 1– 13 Xia Y, Zweier JL. Direct measurement of nitric oxide generation from nitric oxide synthase. Proc Natl Acad Sci USA 1997; 94: 12705–10 Girotti AW. Lipid hydroperoxide generation, turnover, and effector action in biological systems. J Lipid Res 1998; 39: 1529– 42 Gueraud F, Atalay M, Bresgen N, et al. Chemistry and biochemistry of lipid peroxidation products. Free Radic Res 2010; 44: 1098– 124 Esterbauer H. Cytotoxicity and genotoxicity of lipid-oxidation products. Am J Clin Nutr 1993; 57(5 Suppl.): 779–85S; discussion 85S– 6S Frankel EN. Secondary products of lipid oxidation. Chem Phys Lipids 1987; 44: 73– 85 Sanada S, Komuro I, Kitakaze M. Pathophysiology of myocardial reperfusion injury: pre-conditioning, post-conditioning, and translational aspects of protective measures. Am J Physiol Heart Circ Physiol 2011; 301: H1723–41

18 Ruiz-Meana M, Abellan A, Miro-Casas E, Agullo E, Garcia-Dorado D. Role of sarcoplasmic reticulum in mitochondrial permeability transition and cardiomyocyte death during reperfusion. Am J Physiol Heart Circ Physiol 2009; 297: H1281–9 19 Benhabbouche S, Crola da Silva C, Abrial M, Ferrera R. The basis of ischemia –reperfusion and myocardial protection. Ann Fr Anesth Reanim 2011; 30(Suppl. 1): S2– 16 20 Raedschelders K, Ansley DM, Chen DD. The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion. Pharmacol Ther 2012; 133: 230– 55 21 Kalogeris T, Baines CP, Krenz M, Korthuis RJ. Cell biology of ischemia/reperfusion injury. Int Rev Cell Mol Biol 2012; 298: 229–317 22 Parks DA, Granger DN. Contributions of ischemia and reperfusion to mucosal lesion formation. Am J Physiol 1986; 250(6 Pt 1): G749– 53 23 Parks DA, Granger DN. Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand Suppl 1986; 548: 87– 99 24 Penna C, Tullio F, Perrelli MG, et al. Ischemia/reperfusion injury is increased and cardioprotection by a post-conditioning protocol is lost as cardiac hypertrophy develops in nandrolone treated rats. Basic Res Cardiol 2011; 106: 409– 20 25 Kim JS, Jin Y, Lemasters JJ. Reactive oxygen species, but not Ca2+ overloading, trigger pH- and mitochondrial permeability transitiondependent death of adult rat myocytes after ischemia– reperfusion. Am J Physiol Heart Circ Physiol 2006; 290: H2024–34 26 Di Lisa F, Canton M, Carpi A, et al. Mitochondrial injury and protection in ischemic pre- and post-conditioning. Antioxid Redox Signal 2011; 14: 881– 91 27 Loor G, Kondapalli J, Iwase H, et al. Mitochondrial oxidant stress triggers cell death in simulated ischemia–reperfusion. Biochim Biophys Acta 2011; 1813: 1382–94 28 Murphy E, Steenbergen C. What makes the mitochondria a killer? Can we condition them to be less destructive? Biochim Biophys Acta 2011; 1813: 1302–8 29 Hausenloy DJ, Yellon DM. The mitochondrial permeability transition pore: its fundamental role in mediating cell death during ischaemia and reperfusion. J Mol Cell Cardiol 2003; 35: 339– 41 30 Griffiths EJ, Halestrap AP. Protection by Cyclosporin A of ischemia/ reperfusion-induced damage in isolated rat hearts. J Mol Cell Cardiol 1993; 25: 1461– 9 31 Dean RT, Fu S, Stocker R, Davies MJ. Biochemistry and pathology of radical-mediated protein oxidation. Biochem J 1997; 324(Pt 1): 1– 18 32 Joffe A, Geacintov NE, Shafirovich V. DNA lesions derived from the site selective oxidation of Guanine by carbonate radical anions. Chem Res Toxicol 2003; 16: 1528–38 33 Wolff SP, Dean RT. Fragmentation of proteins by free radicals and its effect on their susceptibility to enzymic hydrolysis. Biochem J 1986; 234: 399– 403 34 Pratt DA, Tallman KA, Porter NA. Free radical oxidation of polyunsaturated lipids: new mechanistic insights and the development of peroxyl radical clocks. Acc Chem Res 2011; 44: 458–67 35 Simonelli V, Mazzei F, D’Errico M, Dogliotti E. Gene susceptibility to oxidative damage: from single nucleotide polymorphisms to function. Mutat Res 2012; 731: 1– 13 36 Cadet J, Douki T, Gasparutto D, Ravanat JL. Oxidative damage to DNA: formation, measurement and biochemical features. Mutat Res 2003; 531: 5 –23 37 Davies KJ. Protein damage and degradation by oxygen radicals. I. general aspects. J Biol Chem 1987; 262: 9895– 901 38 Deigner HP, Hermetter A. Oxidized phospholipids: emerging lipid mediators in pathophysiology. Curr Opin Lipidol 2008; 19: 289– 94

Page 9 of 13

Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014

Declaration of interest

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59 Lecour S. Activation of the protective Survivor Activating Factor Enhancement (SAFE) pathway against reperfusion injury: does it go beyond the RISK pathway? J Mol Cell Cardiol 2009; 47: 32 –40 60 Zhou X, Zhai X, Ashraf M. Direct evidence that initial oxidative stress triggered by pre-conditioning contributes to second window of protection by endogenous antioxidant enzyme in myocytes. Circulation 1996; 93: 1177– 84 61 Date T, Mochizuki S, Belanger AJ, et al. Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia– reperfusion injury. Am J Physiol Cell Physiol 2005; 288: C314–20 62 Loor G, Schumacker PT. Role of hypoxia-inducible factor in cell survival during myocardial ischemia– reperfusion. Cell Death Differ 2008; 15: 686– 90 63 Koh MY, Powis G. Passing the baton: the HIF switch. Trends Biochem Sci 2012; 37: 364– 72 64 Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler AA III. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ Res 2006; 98: 133– 40 65 Adluri RS, Thirunavukkarasu M, Dunna NR, et al. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-12/2) attenuates ex vivo myocardial ischemia/ reperfusion injury through hypoxia-inducible factor-1alpha transcription factor and its target genes in mice. Antioxid Redox Signal 2011; 15: 1789–97 66 Cao Z, Liu L, Van Winkle DM. Activation of delta- and kappa-opioid receptors by opioid peptides protects cardiomyocytes via KATP channels. Am J Physiol Heart Circ Physiol 2003; 285: H1032– 9 67 Methner C, Schmidt K, Cohen MV, Downey JM, Krieg T. Both A2a and A2b adenosine receptors at reperfusion are necessary to reduce infarct size in mouse hearts. Am J Physiol Heart Circ Physiol 2010; 299: H1262– 4 68 Xin W, Yang X, Rich TC, et al. All pre-conditioning-related G proteincoupled receptors can be demonstrated in the rabbit cardiomyocyte. J Cardiovasc Pharmacol Ther 2012; 17: 190– 8 69 Ma MC, Qian H, Ghassemi F, Zhao P, Xia Y. Oxygen-sensitive {delta}-opioid receptor-regulated survival and death signals: novel insights into neuronal pre-conditioning and protection. J Biol Chem 2005; 280: 16208– 18 70 Eisinger DA, Ammer H. Epidermal growth factor treatment switches delta-opioid receptor-stimulated extracellular signalregulated kinases 1 and 2 signaling from an epidermal growth factor to an insulin-like growth factor-1 receptor-dependent mechanism. Mol Pharmacol 2011; 79: 326–35 71 Williams-Pritchard G, Knight M, Hoe LS, Headrick JP, Peart JN. Essential role of EGFR in cardioprotection and signaling responses to A1 adenosine receptors and ischemic pre-conditioning. Am J Physiol Heart Circ Physiol 2011; 300: H2161–8 72 Methner C, Donat U, Felix SB, Krieg T. Cardioprotection of bradykinin at reperfusion involves transactivation of the epidermal growth factor receptor via matrix metalloproteinase-8. Acta Physiol (Oxf) 2009; 197: 265– 71 73 Nakamura M, Nakakimura K, Matsumoto M, Sakabe T. Rapid tolerance to focal cerebral ischemia in rats is attenuated by adenosine A1 receptor antagonist. J Cereb Blood Flow Metab 2002; 22: 161–70 74 Belcheva MM, Vogel Z, Ignatova E, et al. Opioid modulation of extracellular signal-regulated protein kinase activity is rasdependent and involves Gbetagamma subunits. J Neurochem 1998; 70: 635– 45 75 Germack R, Dickenson JM. Adenosine triggers pre-conditioning through MEK/ERK1/2 signalling pathway during hypoxia/

Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014

39 Forman HJ, Fukuto JM, Miller T, Zhang HQ, Rinna A, Levy S. The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal. Arch Biochem Biophys 2008; 477: 183–95 40 Tritto I, Ambrosio G. Role of oxidants in the signaling pathway of pre-conditioning. Antioxid Redox Signal 2001; 3: 3– 10 41 Penna C, Mancardi D, Rastaldo R, Pagliaro P. Cardioprotection: a radical view free radicals in pre and post-conditioning. BBABioenergetics 2009; 1787: 781–93 42 Jiang F, Zhang Y, Dusting GJ. NADPH oxidase-mediated redox signaling: roles in cellular stress response, stress tolerance, and tissue repair. Pharmacol Rev 2011; 63: 218–42 43 Penna C, Rastaldo R, Mancardi D, et al. Post-conditioning induced cardioprotection requires signaling through a redox-sensitive mechanism, mitochondrial ATP-sensitive K+ channel and protein kinase C activation. Basic Res Cardiol 2006; 101: 180–9 44 Murry CE, Jennings RB, Reimer KA. Pre-conditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 1986; 74: 1124– 36 45 Zhao ZQ, Corvera JS, Halkos ME, et al. Inhibition of myocardial injury by ischemic post-conditioning during reperfusion: comparison with ischemic pre-conditioning. Am J Physiol Heart Circ Physiol 2003; 285: H579–88 46 Kin H, Zhao ZQ, Sun HY, et al. Post-conditioning attenuates myocardial ischemia –reperfusion injury by inhibiting events in the early minutes of reperfusion. Cardiovasc Res 2004; 62: 74 –85 47 Haroun-Bizri S, Khoury SS, Chehab IR, Kassas CM, Baraka A. Does isoflurane optimize myocardial protection during cardiopulmonary bypass? J Cardiothorac Vasc Anesth 2001; 15: 418–21 48 Durdu S, Sirlak M, Cetintas D, et al. The efficacies of modified mechanical post conditioning on myocardial protection for patients undergoing coronary artery bypass grafting. J Cardiothorac Surg 2012; 7: 73 49 Staat P, Rioufol G, Piot C, et al. Post-conditioning the human heart. Circulation 2005; 112: 2143– 8 50 Yang XC, Liu Y, Wang LF, et al. Reduction in myocardial infarct size by post-conditioning in patients after percutaneous coronary intervention. J Invasive Cardiol 2007; 19: 424– 30 51 Ma X, Zhang X, Li C, Luo M. Effect of post-conditioning on coronary blood flow velocity and endothelial function and LV recovery after myocardial infarction. J Interv Cardiol 2006; 19: 367– 75 52 Tritto I, D’Andrea D, Eramo N, et al. Oxygen radicals can induce preconditioning in rabbit hearts. Circ Res 1997; 80: 743–8 53 Tanaka M, Fujiwara H, Yamasaki K, Sasayama S. Superoxide dismutase and N-2-mercaptopropionyl glycine attenuate infarct size limitation effect of ischaemic pre-conditioning in the rabbit. Cardiovasc Res 1994; 28: 980–6 54 Vigneron F, Dos Santos P, Lemoine S, et al. GSK-3beta at the crossroads in the signalling of heart pre-conditioning: implication of mTOR and Wnt pathways. Cardiovasc Res 2011; 90: 49 –56 55 Argaud L, Gateau-Roesch O, Raisky O, Loufouat J, Robert D, Ovize M. Post-conditioning inhibits mitochondrial permeability transition. Circulation 2005; 111: 194–7 56 Jin C, Wu J, Watanabe M, Okada T, Iesaki T. Mitochondrial K+ channels are involved in ischemic post-conditioning in rat hearts. J Physiol Sci 2012; 62: 325–32 57 Penna C, Mancardi D, Rastaldo R, Losano G, Pagliaro P. Intermittent activation of bradykinin B2 receptors and mitochondrial KATP channels trigger cardiac post-conditioning through redox signaling. Cardiovasc Res 2007; 75: 168–77 58 Xue Y, Xie N, Lin Y, et al. Role of PI3 K/Akt in diazoxide preconditioning against rat hippocampal neuronal death in pilocarpine-induced seizures. Brain Res 2011; 1383: 135– 40

Pac-Soo et al.

Pre- and post-conditioning

76

77

78

80

81 82 83

84 85

86

87

88

89

90

91

92

93

94 Juhaszova M, Zorov DB, Kim SH, et al. Glycogen synthase kinase-3 beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest 2004; 113: 1535–49 95 Cohen P, Frame S. The renaissance of GSK3. Nat Rev Mol Cell Biol 2001; 2: 769– 76 96 Gingras AC, Raught B, Sonenberg N. Regulation of translation initiation by FRAP/mTOR. Genes Dev 2001; 15: 807– 26 97 Jang HS, Kim J, Kim KY, Kim JI, Cho MH, Park KM. Previous ischemia and reperfusion injury results in resistance of the kidney against subsequent ischemia and reperfusion insult in mice; a role for the Akt signal pathway. Nephrol Dial Transplant 2012; 27: 3762– 70 98 Wu QL, Shen T, Shao LL, Ma H, Wang JK. Ischemic postconditioning mediates cardioprotection via PI3 K/GSK-3beta/ beta-catenin signaling pathway in ischemic rat myocardium. Shock 2012; 38: 165– 9 99 Zhu M, Feng J, Lucchinetti E, et al. Ischemic post-conditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res 2006; 72: 152– 62 100 Ma XJ, Yin HJ, Guo CY, Jiang YR, Wang JS, Shi DZ. Ischemic postconditioning through percutaneous transluminal coronary angioplasty in pigs: roles of PI3 K activation. Coron Artery Dis 2012; 23: 245– 50 101 Wagner C, Tillack D, Simonis G, Strasser RH, Weinbrenner C. Ischemic post-conditioning reduces infarct size of the in vivo rat heart: role of PI3-K, mTOR, GSK-3beta, and apoptosis. Mol Cell Biochem 2010; 339: 135– 47 102 Sivaraman V, Mudalagiri NR, Di Salvo C, et al. Post-conditioning protects human atrial muscle through the activation of the RISK pathway. Basic Res Cardiol 2007; 102: 453–9 103 Darling CE, Jiang R, Maynard M, Whittaker P, Vinten-Johansen J, Przyklenk K. Post-conditioning via stuttering reperfusion limits myocardial infarct size in rabbit hearts: role of ERK1/2. Am J Physiol Heart Circ Physiol 2005; 289: H1618– 26 104 Eldaif SM, Deneve JA, Wang NP, et al. Attenuation of renal ischemia– reperfusion injury by post-conditioning involves adenosine receptor and protein kinase C activation. Transpl Int 2010; 23: 217– 26 105 Zhan E, McIntosh VJ, Lasley RD. Adenosine A(2)A and A(2)B receptors are both required for adenosine A(1) receptor-mediated cardioprotection. Am J Physiol Heart Circ Physiol 2011; 301: H1183– 9 106 Kin H, Zatta AJ, Lofye MT, et al. Post-conditioning reduces infarct size via adenosine receptor activation by endogenous adenosine. Cardiovasc Res 2005; 67: 124– 33 107 Yang XM, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV. Attenuation of infarction in cynomolgus monkeys: pre-conditioning and post-conditioning. Basic Res Cardiol 2010; 105: 119–28 108 Yellon DM, Baxter GF. Reperfusion injury revisited: is there a role for growth factor signaling in limiting lethal reperfusion injury? Trends Cardiovasc Med 1999; 9: 245– 9 109 Hausenloy DJ, Tsang A, Yellon DM. The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and post-conditioning. Trends Cardiovasc Med 2005; 15: 69–75 110 Yu X, Deng LY, Wang D, et al. Mechanism of TNF-alpha autocrine effects in hypoxic cardiomyocytes: Initiated by hypoxia inducible factor 1 alpha, presented by exosomes. J Mol Cell Cardiol 2012; 53: 848– 57 111 Sugano M, Tsuchida K, Hata T, Makino N. In vivo transfer of soluble TNF-alpha receptor 1 gene improves cardiac function and reduces infarct size after myocardial infarction in rats. FASEB J 2004; 18: 911– 3

Page 11 of 13

Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014

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reoxygenation in neonatal rat cardiomyocytes. J Mol Cell Cardiol 2005; 39: 429– 42 Cohen MV, Philipp S, Krieg T, et al. Pre-conditioning-mimetics bradykinin and DADLE activate PI3-kinase through divergent pathways. J Mol Cell Cardiol 2007; 42: 842–51 Yoshida M, Nakakimura K, Cui YJ, Matsumoto M, Sakabe T. Adenosine A(1) receptor antagonist and mitochondrial ATPsensitive potassium channel blocker attenuate the tolerance to focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2004; 24: 771–9 Pardo OE, Arcaro A, Salerno G, Raguz S, Downward J, Seckl MJ. Fibroblast growth factor-2 induces translational regulation of Bcl-XL and Bcl-2 via a MEK-dependent pathway: correlation with resistance to etoposide-induced apoptosis. J Biol Chem 2002; 277: 12040–6 Bryckaert M, Guillonneau X, Hecquet C, Courtois Y, Mascarelli F. Both FGF1 and bcl-x synthesis are necessary for the reduction of apoptosis in retinal pigmented epithelial cells by FGF2: role of the extracellular signal-regulated kinase 2. Oncogene 1999; 18: 7584–93 Jourdain A, Martinou JC. Mitochondrial outer-membrane permeabilization and remodelling in apoptosis. Int J Biochem Cell Biol 2009; 41: 1884– 9 Kale J, Liu Q, Leber B, Andrews DW. Shedding light on apoptosis at subcellular membranes. Cell 2012; 151: 1179– 84 Martinou JC, Youle RJ. Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 2011; 21: 92– 101 Gross ER, Hsu AK, Gross GJ. Opioid-induced cardioprotection occurs via glycogen synthase kinase beta inhibition during reperfusion in intact rat hearts. Circ Res 2004; 94: 960–6 Bos JL. A target for phosphoinositide 3-kinase: Akt/PKB. Trends Biochem Sci 1995; 20: 441– 2 Marte BM, Downward J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 1997; 22: 355–8 Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261– 9 Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol 2005; 288: H971–6 Kunuthur SP, Mocanu MM, Hemmings BA, Hausenloy DJ, Yellon DM. The Akt1 isoform is an essential mediator of ischaemic preconditioning. J Cell Mol Med 2012; 16: 1739–49 Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995; 378: 785–9 Olianas MC, Dedoni S, Onali P. Signaling pathways mediating phosphorylation and inactivation of glycogen synthase kinase-3 beta by the recombinant human delta-opioid receptor stably expressed in Chinese hamster ovary cells. Neuropharmacology 2011; 60: 1326– 36 Tong H, Imahashi K, Steenbergen C, Murphy E. Phosphorylation of glycogen synthase kinase-3beta during pre-conditioning through a phosphatidylinositol-3-kinase-dependent pathway is cardioprotective. Circ Res 2002; 90: 377–9 Nishihara M, Miura T, Miki T, et al. Modulation of the mitochondrial permeability transition pore complex in GSK-3beta-mediated myocardial protection. J Mol Cell Cardiol 2007; 43: 564–70 Terashima Y, Sato T, Yano T, et al. Roles of phospho-GSK-3beta in myocardial protection afforded by activation of the mitochondrial K ATP channel. J Mol Cell Cardiol 2010; 49: 762– 70

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131 Costa AD, Garlid KD. Intramitochondrial signaling: interactions among mitoKATP, PKCepsilon, ROS, and MPT. Am J Physiol Heart Circ Physiol 2008; 295: H874–82 132 Wang ZH, Chen YX, Zhang CM, et al. Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion. Am J Physiol Heart Circ Physiol 2011; 301: H1695– 705 133 Garg V, Hu K. Protein kinase C isoform-dependent modulation of ATP-sensitive K+ channels in mitochondrial inner membrane. Am J Physiol Heart Circ Physiol 2007; 293: H322–32 134 Mykytenko J, Reeves JG, Kin H, et al. Persistent beneficial effect of post-conditioning against infarct size: role of mitochondrial K(ATP) channels during reperfusion. Basic Res Cardiol 2008; 103: 472– 84 135 Quinlan CL, Costa AD, Costa CL, Pierre SV, Dos Santos P, Garlid KD. Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels. Am J Physiol Heart Circ Physiol 2008; 295: H953– 61 136 Costa AD, Jakob R, Costa CL, Andrukhiv K, West IC, Garlid KD. The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition. J Biol Chem 2006; 281: 20801– 8 137 Okubo S, Tanabe Y, Fujioka N, Takeda K, Takekoshi N. Differential activation of protein kinase C between ischemic and pharmacological pre-conditioning in the rabbit heart. Jpn J Physiol 2003; 53: 173– 80 138 Oldenburg O, Qin Q, Krieg T, et al. Bradykinin induces mitochondrial ROS generation via NO, cGMP, PKG, and mitoKATP channel opening and leads to cardioprotection. Am J Physiol Heart Circ Physiol 2004; 286: H468– 76 139 Costa AD, Quinlan CL, Andrukhiv A, West IC, Jaburek M, Garlid KD. The direct physiological effects of mitoK(ATP) opening on heart mitochondria. Am J Physiol Heart Circ Physiol 2006; 290: H406– 15 140 Andrukhiv A, Costa AD, West IC, Garlid KD. Opening mitoKATP increases superoxide generation from complex I of the electron transport chain. Am J Physiol Heart Circ Physiol 2006; 291: H2067–74 141 McPherson BC, Yao Z. Morphine mimics pre-conditioning via free radical signals and mitochondrial K(ATP) channels in myocytes. Circulation 2001; 103: 290– 5 142 Jebeli M, Esmaili HR, Mandegar MH, et al. Evaluation of the effects of ischemic pre-conditioning with a short reperfusion phase on patients undergoing a coronary artery bypass graft. Ann Thorac Cardiovasc Surg 2010; 16: 248–52 143 Jenkins DP, Pugsley WB, Alkhulaifi AM, Kemp M, Hooper J, Yellon DM. Ischaemic pre-conditioning reduces troponin T release in patients undergoing coronary artery bypass surgery. Heart 1997; 77: 314–8 144 Garcia S, Henry TD, Wang YL, et al. Long-term follow-up of patients undergoing post-conditioning during ST-elevation myocardial infarction. J Cardiovasc Transl Res 2011; 4: 92– 8 145 Xue F, Yang X, Zhang B, et al. Post-conditioning the human heart in percutaneous coronary intervention. Clin Cardiol 2010; 33: 439– 44 146 Thuny F, Lairez O, Roubille F, et al. Post-conditioning reduces infarct size and edema in patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol 2012; 59: 2175– 81 147 Tarantini G, Favaretto E, Marra MP, et al. Post-conditioning during coronary angioplasty in acute myocardial infarction: the POST-AMI trial. Int J Cardiol 2012; 162: 33 –8

Downloaded from http://bja.oxfordjournals.org/ at University of California, San Francisco on September 26, 2014

112 Lecour S, Suleman N, Deuchar GA, et al. 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 2005; 112: 3911–8 113 Suleman N, Somers S, Smith R, Opie LH, Lecour SC. Dual activation of STAT-3 and Akt is required during the trigger phase of ischaemic pre-conditioning. Cardiovasc Res 2008; 79: 127– 33 114 Lecour S. Multiple protective pathways against reperfusion injury: a SAFE path without Aktion? J Mol Cell Cardiol 2009; 46: 607– 9 115 Huffman LC, Koch SE, Butler KL. Coronary effluent from a preconditioned heart activates the JAK-STAT pathway and induces cardioprotection in a donor heart. Am J Physiol Heart Circ Physiol 2008; 294: H257–62 116 Goodman MD, Koch SE, Afzal MR, Butler KL. STAT subtype specificity and ischemic pre-conditioning in mice: is STAT-3 enough? Am J Physiol Heart Circ Physiol 2011; 300: H522–6 117 Goodman MD, Koch SE, Fuller-Bicer GA, Butler KL. Regulating RISK: a role for JAK-STAT signaling in post-conditioning? Am J Physiol Heart Circ Physiol 2008; 295: H1649– 56 118 Lacerda L, Somers S, Opie LH, Lecour S. Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 2009; 84: 201– 8 119 Hattori R, Maulik N, Otani H, et al. Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol 2001; 33: 1929– 36 120 Uchiyama Y, Otani H, Wakeno M, et al. Role of mitochondrial KATP channels and protein kinase C in ischaemic pre-conditioning. Clin Exp Pharmacol Physiol 2003; 30: 426–36 121 Donato M, D’Annunzio V, Berg G, et al. Ischemic post-conditioning reduces infarct size by activation of A1 receptors and K+(ATP) channels in both normal and hypercholesterolemic rabbits. J Cardiovasc Pharmacol 2007; 49: 287–92 122 Ghosh S, Standen NB, Galinanes M. Evidence for mitochondrial K ATP channels as effectors of human myocardial pre-conditioning. Cardiovasc Res 2000; 45: 934– 40 123 Maslov LN, Lishmanov YB, Oeltgen PR, et al. Activation of peripheral delta2 opioid receptors increases cardiac tolerance to ischemia/reperfusion injury involvement of protein kinase C, NO-synthase, KATP channels and the autonomic nervous system. Life Sci 2009; 84: 657– 63 124 Wang L, Zhu QL, Wang GZ, et al. The protective roles of mitochondrial ATP-sensitive potassium channels during hypoxia– ischemia– reperfusion in brain. Neurosci Lett 2011; 491: 63– 7 125 Liang BT, Gross GJ. Direct pre-conditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res 1999; 84: 1396– 400 126 Raval AP, Dave KR, DeFazio RA, Perez-Pinzon MA. epsilonPKC phosphorylates the mitochondrial K(+) (ATP) channel during induction of ischemic pre-conditioning in the rat hippocampus. Brain Res 2007; 1184: 345– 53 127 Pain T, Yang XM, Critz SD, et al. Opening of mitochondrial K(ATP) channels triggers the preconditioned state by generating free radicals. Circ Res 2000; 87: 460–6 128 Reshef A, Sperling O, Zoref-Shani E. Opening of K(ATP) channels is mandatory for acquisition of ischemic tolerance by adenosine. Neuroreport 2000; 11: 463–5 129 Miura T, Liu Y, Kita H, Ogawa T, Shimamoto K. Roles of mitochondrial ATP-sensitive K channels and PKC in anti-infarct tolerance afforded by adenosine A1 receptor activation. J Am Coll Cardiol 2000; 35: 238– 45 130 Garlid KD, Costa AD, Quinlan CL, Pierre SV, Dos Santos P. Cardioprotective signaling to mitochondria. J Mol Cell Cardiol 2009; 46: 858– 66

Pac-Soo et al.

Pre- and post-conditioning

157 Loukogeorgakis SP, Williams R, Panagiotidou AT, et al. Transient limb ischemia induces remote pre-conditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation 2007; 116: 1386–95 158 Zhou Y, Fathali N, Lekic T, et al. Remote limb ischemic postconditioning protects against neonatal hypoxic– ischemic brain injury in rat pups by the opioid receptor/Akt pathway. Stroke 2011; 42: 439– 44 159 Cheung MM, Kharbanda RK, Konstantinov IE, et al. Randomized controlled trial of the effects of remote ischemic pre-conditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 2006; 47: 2277– 82 160 Hausenloy DJ, Mwamure PK, Venugopal V, et al. Effect of remote ischaemic pre-conditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 2007; 370: 575–9 161 Brevoord D, Kranke P, Kuijpers M, Weber N, Hollmann M, Preckel B. Remote ischemic conditioning to protect against ischemia– reperfusion injury: a systematic review and meta-analysis. PLoS One 2012; 7: e42179 162 Li L, Li G, Yu C, Li Y. The role of remote ischemic pre-conditioning on postoperative kidney injury in patients undergoing cardiac and vascular interventions: a meta-analysis. J Cardiothorac Surg 2013; 8: 43 163 Hoole SP, Heck PM, Sharples L, et al. Cardiac Remote Ischemic Preconditioning in Coronary Stenting (CRISP Stent) study: a prospective, randomized control trial. Circulation 2009; 119: 820– 7 164 Davies WR, Brown AJ, Watson W, et al. Remote ischemic pre-conditioning improves outcome at 6 years after elective percutaneous coronary intervention: the CRISP stent trial long-term follow-up. Circ Cardiovasc Interv 2013; 6: 246– 51 165 Lavi S, D’Alfonso S, Diamantouros P, et al. Remote ischemic post-conditioning during percutaneous coronary interventions: remote ischemic post-conditioning-percutaneous coronary intervention randomized trial. Circ Cardiovasc Interv 2014; 7: 225–32

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148 Brooks MJ, Andrews DT. Molecular mechanisms of ischemic conditioning: translation into patient outcomes. Future Cardiol 2013; 9: 549– 68 149 Sabbagh S, Henry Salzman MM, Kloner RA, Simkhovich BZ, Rezkalla SH. Remote ischemic pre-conditioning for coronary artery bypass graft operations. Ann Thorac Surg 2013; 96: 727– 36 150 Kottenberg E, Thielmann M, Bergmann L, et al. Protection by remote ischemic pre-conditioning during coronary artery bypass graft surgery with isoflurane but not propofol—a clinical trial. Acta Anaesthesiol Scand 2012; 56: 30–8 151 Thielmann M, Kottenberg E, Kleinbongard P, et al. Cardioprotective and prognostic effects of remote ischaemic pre-conditioning in patients undergoing coronary artery bypass surgery: a singlecentre randomised, double-blind, controlled trial. Lancet 2013; 382: 597–604 152 D’Ascenzo F, Cavallero E, Moretti C, et al. Remote ischaemic preconditioning in coronary artery bypass surgery: a meta-analysis. Heart 2012; 98: 1267– 71 153 Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P. Regional ischemic ‘pre-conditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 1993; 87: 893– 9 154 Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK. Remote post-conditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3 K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol 2011; 106: 135–45 155 Li J, Xuan W, Yan R, et al. Remote pre-conditioning provides potent cardioprotection via PI3 K/Akt activation and is associated with nuclear accumulation of beta-catenin. Clin Sci (Lond) 2011; 120: 451– 62 156 Dickson EW, Lorbar M, Porcaro WA, et al. Rabbit heart can be ‘preconditioned’ via transfer of coronary effluent. Am J Physiol 1999; 277(6 Pt 2): H2451–7

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