DELAYED PRECONDITIONING AND ADAPTIVE CARDIOPROTECTION Developments in Cardiovascular Medicine VOLUME 207 The titles published in this series are listed at the end of this volume. DDeellaayyeedd PPrreeccoonnddiittiioonniinngg aanndd AAddaappttiivvee CCaarrddiioopprrootteeccttiioonn eeddiitteeddbbyy GG.. FF.. BBAAXXTTEERR TThhee HHaatttteerr IInnssttiittuuttee ffoorr CCaarrddiioovvaassccuullaarr SSttuuddiieess,, UUnniivveerrssiittyy CCooll//eeggee LLoonnddoonn MMeeddiiccaall SScchhooooll,, LLoonnddoonn,, UU..KK.. aanndd DD.. MM.. YYEELLLLOONN TThhee HHaatttteerr IInnssttiittuuttee ffoorr CCaarrddiioovvaassccuullaarr SSttuuddiieess,, UUnniivveerrssiittyy CCooll//eeggee LLoonnddoonn MMeeddiiccaall SSCChhooooll,, LLoonnddoonn,, uu..KK.. SSPPRRIINNGGEERR--SSCCIIEENNCCEE++BBUUSSIINNEESSSS MMEEDDIIAA,, BB..VV.. AA CC..!!..PP.. CCaattaalloogguuee rreeccoorrdd ffoorr tthhiiss bbooookk iiss aavvaaiillaabbllee ffrroomm tthhee LLiibbrraarryy ooff CCoonnggrreessss.. IISSBBNN 997788--9944--001100--66223311--22 IISSBBNN 997788--9944--001111--55331122--66 ((eeBBooookk)) DDOOII 1100..11000077//997788--9944--001111--55331122--66 PPrriinntteedd oonn aacciidd--ffrreeee ppaappeerr CCoovveerr ddrraawwiinngg bbyy DDrr RRoobbeerrtt BBeeIIII AAIIII RRiigghhttss RReesseerrvveedd ©©11999988 SSpprriinnggeerr SScciieennccee++BBuussiinneessss MMeeddiiaa DDoorrddrreecchhtt OOrriiggiinnaallllyy ppuubblliisshheedd bbyy KKlluuwweerr AAccaaddeemmiicc PPuubblliisshheerrss iinn 11999988 SSooffttccoovveerr rreepprriinntt ooff tthhee hhaarrddccoovveerr 11sstt eeddiittiioonn 11999988 NNoo ppaarrtt ooff tthhee mmaatteerriiaall pprrootteecctteedd bbyy tthhiiss ccooppyyrriigghhtt nnoottiiccee mmaayy bbee rreepprroodduucceedd oorr uuttiilliizzeedd iinn aannyy ffoorrmm oorr bbyy aannyy mmeeaannss,, eelleeccttrroonniicc oorr mmeecchhaanniiccaall,, iinncclluuddiinngg pphhoottooccooppyyiinngg,, rreeccoorrddiinngg oorr bbyy aannyy iinnffoorrmmaattiioonn ssttoorraaggee aanndd rreettrriieevvaall ssyysstteemm,, wwiitthhoouutt wwrriitttteenn ppeerrmmiissssiioonn ffrroomm tthhee ccooppyyrriigghhtt oowwnneerr Contents Contributors xv Preface Xl Acknowledgements xiii 1 Delayed Preconditioning Against Lethal Ischaemic Injury G F Baxter and D MYel/on 1 1. Introduction 1 2. Background 2 3. Discovery of Delayed Preconditioning 2 4. Characteristics of Delayed Preconditioning Against Infarction 6 5. Delayed Preconditioning Against Myocyte Injury In Vitro 12 6. Delayed Preconditioning Against Ischaemic Injury in Other Tissues 13 7. Mechanisms of Delayed Preconditioning 13 8. Triggers of Adaptation in Delayed Preconditioning 15 9. Signal Transduction in Delayed Preconditioning 16 10. Downstream Mediators and Possible Effectors of Protection 18 11. Conclusions 21 References 22 2 Delayed Preconditioning Against Myocardial Stunning R Bolli, B Dawn, X-L Tang, Y Qiu, P Ping, J Zhang and H Takano 29 1. Introduction 29 2. Pathophysiology of Late Preconditioning Against Stunning 30 3. The Preconditioning Stimulus or 'Trigger' of Late PC 32 4. The Signal Transduction Pathways of Late PC 36 5. The Mediator(s) of the Protective Effects of Late PC 37 vi CONTENTS 6. The Nitric Oxide Hypothesis of Late PC 40 7. Conclusions 42 References 43 3 Delayed Preconditioning Against Endothelial Dysfunction V Richard, P Beauchamp, N Kaeffer and C Thuillez 47 1. Introduction 47 2. Reperfusion Injury to Endothelial Cells 48 3. Evidence for Delayed Preconditioning of Coronary Endothelial Cells 52 4. Mechanisms of Delayed Protection 53 5. Mediators of Protection 54 6. Triggers of Protection 56 7. Conclusion 58 References 58 4 Delayed Preconditioning Against Ventricular Arrhythmias A Vegh and J R Parratt 63 1. Introduction 63 2. Experimental Background 63 3. From Early to Delayed Protection 65 4. Delayed Protection Against Arrhythmias by Cardiac Pacing 66 5. Time Course and Renewal of Delayed Protection 69 6. Delayed Protection Against Arrhythmias Induced by Prostacyclin 72 7. Delayed Protection Against Arrhythmias Induced by Endotoxins 72 8. Delayed Protection Against Arrhythmias Induced by Catecholamines 73 9. Roles of NO and Bradykinin in Delayed Protection Against Arrhythmias 75 10. Conclusion 79 References 81 5 Intracellular Signalling Mechanisms in Myocardial Adaptation to Ischaemia DKDas 91 1. Introduction 91 2. Stress Adaptation in the Heart 92 CONTENTS vii 3. Signal Transduction Pathways in Adaptation 92 4. Protein Tyrosine Kinase Signalling 92 5. Phospholipase D Signalling 93 6. Protein Kinase C Signalling 96 7. Mitogen Activated Protein Kinases 96 8. p38 MAP Kinase Signalling 97 9. MAPKAP Kinase 2 98 10. Gene Expression 100 11. Conclusion 102 References 103 6 Changes in Cardiac Gene Expression After Ischaemia and Reperfusion L V Mayne 111 1. Introduction 111 2. Methodological Considerations 112 3. Pathophysiological Considerations 112 4. Examination of Gene Regulation 113 5. Transcription Factors 114 6. Cytokines and Growth Factors 120 7. Sarcoplasmic Reticulum Calcium Regulating Proteins 124 8. Antioxidants 125 9. Miscellaneous 125 10. Perspective and Conclusion 126 References 127 7 The Heat Shock Response and Tissue Protection R W Currie and J-C L Plumier 135 1. Introduction 135 2. Heat Shock and HSP70 135 3. Heat Shock, HSP70 and Inducible Cellular Protection in the Heart 136 4. HSP70 Transgenic Mice and Myocardial Protection 138 5. Function of HSP70 139 6. Inducible Cellular Protection in the Brain 139 7. Other Possibilities 141 8. HSP27 and Endogenous Cellular Protection 142 9. HSP27 in the Heart and Brain 143 10. Conclusions 145 References 146 viii CONTENTS 8 Antioxidant Defences in Myocardial Adaptation N Yamashita, T Kuzuya and M Hori 155 1. Introduction 155 2. Sublethal Ischaemia-induced Cardioprotection 156 3. Sublethal Heat Stress-induced Cardioprotection 159 4. Exercise and Cardioprotection 164 5. Production of Oxygen Free Radicals and Biphasic Cardioprotection 165 6. Conclusion 166 References 167 9 Endotoxin, Monophosphoryl Lipid A and Delayed Cardioprotection G J Gross 171 1. Introduction 171 2. Effects of MLA and LPS on Myocardial Infarct Size 173 3. Effects ofMLA andLPS on Myocardial Stunning 174 4. Role of Neutrophils in MLA- and LPS-induced Infarct Size Reduction 176 5. Role of Heat Shock Proteins in MLA- and LPS-induced Cardioprotection 177 6. Role of ATP-Sensitive Potassium Channels (KATP) in MLA- induced Infarct Size Reduction 178 7. Role of KATP Channels in MLA-induced Attenuation of Stunning 180 8. Role of Adenosine in the Cardioprotective Effect of MLA 181 9. Role of NO in MLA-induced Cardioprotection 183 10. Conclusion 183 References 184 10 Adenosine and Delayed Cardioprotection A Dana, D MYel/on and G F Baxter 189 1. Introduction 189 2. Adenosine as a Trigger of Delayed Preconditioning 190 3. Time Course and Maintenance of Adenosine-induced Delayed Cardioprotection 193 4. Signal Transduction Mechanisms 196 5. Distal Mediator(s) of Adenosine-induced Delayed Protection 197 6. Conclusion 201 References 202 CONTENTS ix 11 Angina and Cardiac Adaptation F Ottani, M Galvani and 0 Ferrini 209 1. Introduction 209 2. Preinfarction Angina 209 3. From Experimental Laboratory to Humans 211 4. Pathophysiological Studies 211 5. Retrospective Clinical Studies 214 6. Prospective Clinical Trials 216 7. Preinfarction Angina: Is Preconditioning the Only Mechanism of Protection? 219 8. Conclusion 221 References 221 Index 225 Preface The formal recognition by Charles Murry, Robert Jennings and Keith Reimer in 1986 that myocardium possesses the ability to adapt rapidly to transient ischaemic stress proved to be the impetus for a remarkable explosion in experimental and clinical cardiology research. Many who had previously devoted their valuable time to the investigation of stategies for protection of the ischaemic myocardium were so impressed by the potency of this endogenous cardioprotective response that they opted to examine the phenomenon of myocardial preconditioning in their own laboratories. The results of these investigations have yielded an enormous literature during the last decade. The majority of this work has been devoted to investigating the characteristics and molecular mechanisms of what is now known as the classic preconditioning response originally described by Murry, Jennings and Reimer. In 1993, two reports heralded the recognition of another aspect of myocardial adaptation to ischaemia, namely a delayed preconditioning response which we termed the "second window" of protection. This phenomenon has proved to be of increasing interest because it represents a further feature of the heart's ability to adapt to stressful stimuli. During the last five years, a number of studies have extended the definitions of delayed preconditioning by describing its ability to protect against a variety of ischaemia-reperfusion pathologies. Understanding of the potential triggers, cell signalling pathways and downstream mediators of this sub-acute form of adaptive cardioprotection has advanced considerably in this period. In view of a burgeoning literature, reflecting the interest in delayed preconditioning and related adaptive cardioprotective strategies, we felt it timely to compile a series of state-of-the-art reviews by those people who have made significant contributions to the advance of this field. The chapters contained in this book describe a very rapid advance in delayed preconditioning reseach, from its molecular basis to potential clinical relevance. All of the authors, who are internationally recognised experts, discuss the various aspects of this subject in detail and their