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A Langendorff-Perfused Mouse Heart Model for Delayed Remote Limb Ischemic Preconditioning Studies

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A Langendorff-Perfused Mouse Heart Model for Delayed Remote Limb Ischemic Preconditioning Studies A Langendorff-Perfused Mouse Heart Model For Delayed Remote Limb Ischemic Preconditioning Studies By Sagar Rohailla A thesis submitted in conformity with the requirements for the degree of Masters of Science Institute of Medical Science University of Toronto © Copyright by Sagar Rohailla (2012) A Langendorff-Perfused Mouse Heart Model for Delayed Remote Limb Ischemic Preconditioning Studies Sagar Rohailla Master of Science Institute of Medical Science University of Toronto 2012 Abstract Remote ischemic preconditioning (rIPC) through transient limb ischemia induces potent cardioprotection against ischemia reperfusion (IR) injury. I examined the delayed phase of protection that appears 24 hours after the initial rIPC stimulus. The primary objective of this study was to establish a mode of sedation and control treatment for delayed rIPC experiments. I used an ex-vivo, Langendorff isolated-mouse heart preparation of IR injury to examine the delayed effects of an intra-peritoneal (IP) injection, sodium-pentobarbital (SP), halothane and nitrous oxide (N2O) anesthesia on post-ischemic cardiac function. Each anesthetic method improved left-ventricular function after IR injury. SP and halothane anesthesia also reduced LV infarct size. Delayed cardioprotection after IP injections was associated with an increase in phosphorylated-Akt levels. The present study shows that IP injections and inhalational anesthesia invoke cardioprotection and, therefore, indicates that these modes of sedation should not be used as control treatments for studies examining the delayed rIPC phenotype. ii Acknowledgements First and foremost I would like to thank my supervisor, Dr. Christopher Caldarone for his support throughout this project. I am grateful for all your encouragement and guidance, and for never hesitating to open your door for a chat. Your commitment to ensuring success among your students and your ability to remind us of the bigger picture has always been reassuring. These are qualities I hope to emulate in my future. I would like to thank Dr. Andrew Redington for being a mentor and pillar over the last year. Thank you for believing in me and for giving me the opportunity to develop as a scientist. Working with you has had an immeasurable positive impact on me. I am enormously grateful for the experience. I would like to thank my committee members, Dr. Gregory Wilson and Dr. John Coles for your insight and advice throughout the project. I hope we can work together again in the future. To Dr. Edward Hickey, thank you for being a part of this experience and for connecting me with the field of endotoxin preconditioning. Your PhD thesis was a friendly vision into the world I hope to enter. There are no adequate words to describe the support I received from Dr. Jing Li, Dr. Can Wei and Dr. Xiao Jing Dai. Thank you Dr. Li and Dr. Wei for introducing me to the complexity and beauty of the mouse Langendorff. Thank you for all of the hearts you mounted and cardiac function data you helped me to collect. This project was possible because of your hard work and generosity. I would also like to thank Alex Di Battista for all the support and numerous chats – it has been extremely useful and fun bouncing ideas. Lastly, thank you to Kimberly Elias, friends and my family. You all have been the best academic counselors, companions and sources of support. I am truly thankful to have you in my life. iii Table of Contents Acknowledgements iii Table of Contents iv List of Tables vi List of Figures vii List of Appendices ix List of Abbreviations x Chapter 1: Review of Literature 1 1.1 Introduction: Unexpected Findings 1 1.2 Ischemia Reperfusion Injury 5 1.3 Inflammation and IR Injury 6 1.4 Remote Ischemic Preconditioning 8 1.4.1 Mechanism of rIPC 10 1.5 Reperfusion Injury Salvage Kinases (RISK) 12 1.6 Delayed Preconditioning 15 1.6.1 Mechanism of Delayed Preconditioning 16 1.7 Current models of 2W Preconditioning 17 1.8 Anesthetic Preconditioning 20 1.8.1 Effects of Anesthesia on Heart Function 21 1.8.2 Mechanism of APC 22 1.8.3 Isoflurane 24 1.8.4 Halothane 26 1.8.5 Sevoflurane, Enflurane and Desflurane 27 1.8.6 Nitrous Oxide 27 1.8.7 Intra-peritoneal Anesthesia: Ketamine and Barbiturates 28 1.9 Anesthetic and Ischemic Preconditioning: Clinical Utility 30 1.10 Langendorff Isolated Heart Model of IR Injury 31 Chapter 2: Research Aims and Hypotheses 33 2.1 Summary and Rationale 33 2.2 Research Aims/Objective 34 2.3 Hypotheses 34 Chapter 3: Methods 35 3.1 Ethics 35 3.2 Experimental Groups 35 3.3 Induction of rIPC Using Inguinal Tourniquet Model 38 iv 3.4 A Langendorff Isolated Heart Model of Ischemia-Reperfusion Injury 39 3.5 Infarct Size Determination 43 3.6 Protein Concentration Determination 44 3.7 SDS-Page and Western Blot Analysis 45 3.8 Data and Statistical Analysis 47 Chapter 4: Results 48 4.1 The Delayed Effects of Intra-Peritoneal and Inhalational Anesthesia on Left- Ventricular Function after Global Ischemia 48 4.1.1 Baseline Function 48 4.1.2 Left Ventricular Developed Pressure 50 4.1.3 Left Ventricular End-Diastolic Pressure 55 4.1.4 Maximum Rate of Contraction 60 4.1.5 Maximum Rate of Relaxation 65 4.2 Delayed Preconditioning with Intra-Peritoneal and Inhalational Anesthesia Reduce Infarct Size after IR Injury 69 4.3 Delayed Preconditioning with Injectable and Gas Anesthesia increase phospho-Akt and phospho-p44/42 MAPK Expression 72 Chapter 5: Discussion 76 5.1 Intra-Peritoneal Injections Induce Delayed Preconditioning Against Global IR Injury 78 5.2 Halothane Anesthesia Induces Delayed Preconditioning Against Global IR Injury 82 5.3 Nitrous-Oxide Improves Post-Ischemic Cardiac Performance But Does Not Reduce Infarction Size 83 5.4 Cross-talk between signaling cascades 86 Chapter 6: Conclusions 88 Chapter 7: Future Directions 90 7.1. An In-Vivo Model of Delayed rIPC 91 7.2. Revisiting the role of TLR4 in delayed rIPC 92 7.3. The ‘Third’ Window And Exercise Preconditioning 92 7.4. Clinical Implications of A Mouse Model of Delayed rIPC 93 Chapter 8: References 95 Chapter 9: Appendices 109 v List of Tables 1. Baseline functional parameters in the Langendorff-isolated heart groups for IR injury experiments 49 vi List of Figures 1. Initial study examining the role of TLR4 in Delayed Preconditioning 4 2. Inflammatory response during IR injury: feed-forward cycle 9 3. Schematic representation of mechanisms involved in remote ischemic preconditioning 11 4. Cell signaling mechanisms involved in early and delayed ischemic preconditioning 14 5. The transition between the early and delayed phases of cardioprotection 18 6. A schematic of the study protocol 37 7. Remote ischemic preconditioning (rIPC) via transient ischemia of mouse hindlimb 38 8a. The mouse Langendorff-isolated heart model 40 8b. The mouse Langendorff-isolated heart model used in The Redington Lab 41 9a. The effects of intra-peritoneal anesthesia on post-ischemic left-ventricular developed pressure (LVDP) 52 9b. The effects of inhalational anesthesia on post-ischemic left-ventricular developed pressure (LVDP) 53 9c. Left-ventricular developed pressure (LVDP) at 60 min of reperfusion 54 10a. The effects of intra-peritoneal anesthesia on post-ischemic left-ventricular end-diastolic pressure (LVEDP) 57 10b. The effects of inhalational anesthesia on post-ischemic left-ventricular end-diastolic pressure (LVEDP) 58 10c. Post-ischemic left ventricular end-diastolic pressure (LVEDP) at 60 minutes of reperfusion 59 11a. The effects of intra-peritoneal anesthesia on post-ischemic rate of LV contraction (dP/dtmax) 62 vii 11b. The effects of inhalational anesthesia on post-ischemic rate of LV contraction (dP/dtmax) 63 11c. Post-ischemic rate of LV contraction (dP/dtmax) at 60 minutes of reperfusion 64 12a. The effects of intra-peritoneal anesthesia on post-ischemic rate of LV relaxation (dP/dtmin) 66 12b. The effects of inhalational anesthesia on post-ischemic rate of LV relaxation (dP/dtmin) 67 12c. Post-ischemic rate of LV relaxation (dP/dtmin) at 60 minutes of reperfusion 68 13. The effects of intra-peritoneal and inhalational anesthesia on left-ventricle infarct size after IR injury 70 14. Representative cross-sections of mouse hearts from each treatment group after IR injury 71 15. The effects of intra-peritoneal and inhalational anesthesia on phospho-Akt (Ser473) levels in mouse heart before IR injury 74 16. The effects of intra-peritoneal and inhalational anesthesia on phospho-p44/42 MAPK (Tyr202, Thr204) levels in mouse hearts before IR injury 75 viii List of Appendices 1. Power-lab acquisition software: Cardiac output chart 110 2. Protein extraction-lysis-buffer 110 ix List of Abbreviations 1W First Window 2W Second Window 5-HD 5-Hydroxydecanoate Akt Serine Threonine Kinase- Protein Kinase B AMI Acute Myocardial Infarction AP-1 Activator Protein-1 APC Anesthetic Preconditioning AR Aldose-Reductase 1 ATP Adenosine Triphosphate Ca2+ Calcium Ion CaMKII Ca2+/calmodulin-dependent kinase II CAO Coronary Artery Occlussion COX-2 Cyclooxygenase-II CPB Cardiopulmonary Bypass DAMPs Danger-Associated Molecular Patterns dp/dtmax Maximum Rate of Contraction dp/dtmin Maximum Rate of Relaxation ECL Enhanced Chemiluminescence eNOS Endothelial Nitric-Oxide Synthase GPCR G-Protein Coupled Receptor GSK3β Glycogen Synthase Kinase 3β H+ Hydrogen Ion HMGB High Mobility Group Box 1 HO-I Heme-Oxygenase I HRP Horseradish Peroxidase Hsp27 Heat Shock Protein 27 kDa Hsp70 Heat Shock Protein 70 KDa IGF-1 Insulin Like Growth Factor-1 ICAM1 Intracellular Adhesion Molecule 1 IFN Interferon Il-6 Interleukin-6 Il-8 Interleukin-8 iNOS
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