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Lipoxygenase-Derived Eicosanoids in Myocardial Ischaemia-Reperfusion

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Lipoxygenase-Derived Eicosanoids in Myocardial Ischaemia-Reperfusion Lipoxygenase-derived eicosanoids in myocardial ischaemia-reperfusion injury: the role of sensory C-fibres and TRPV1 Alison Goddard A thesis submitted for the Degree of Doctor of Philosophy University of London 2010 Supervisor: Professor Amrita Ahluwalia Queen Mary University of London Department of Clinical Pharmacology William Harvey Research Institute Charterhouse Square London EC1M 6BQ Email: [email protected] DECLARATION OF OWNERSHIP I declare that the work presented in this thesis is my own. Alison Goddard 2 ABSTRACT It is well established that the 12-lipoxygenase (12-LOX) pathway of arachidonic acid (AA) metabolism is stimulated within the myocardium by episodes of ischaemia, and there is considerable evidence showing that eicosanoids derived via this pathway protect against the damaging effects of myocardial ischaemia-reperfusion (I/R) injury. Recent evidence suggests that transient receptor potential vanilloid receptor 1 (TRPV1), expressed on sensory C-fibres, may play an important protective role against myocardial I/R injury; and in neurones, the 12-LOX metabolite of AA 12(S)- hydroperoxyeicosatetraenoic acid [12(S)-HpETE], has been proposed as an endogenous ligand for TRPV1. However, whether 12(S)-HpETE underlies TRPV1 channel activation during myocardial I/R is unknown. Treatment of isolated Langendorff rat hearts with 12-LOX/AA significantly attenuated I/R injury (~40% inhibition of infarct size), an effect reversed by the 12-LOX inhibitor baicalein or by chemical desensitisation of local C-fibre afferents in vivo using capsaicin. Both 12(S)-HpETE and AA caused dose-dependent coronary vasodilatation (~pEC50s of 18.2 and 6.9, respectively) that was profoundly suppressed by the TRPV1 antagonist capsazepine, or in hearts of TRPV1 knockout mice compared to wild-type mice, or by treatment with the calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP8-37. I/R in vitro reduced expression of myocardial TRPV1 protein, whereas in vivo, TRPV1 protein expression in the heart and dorsal root ganglia (DRG) increased, and DRG TRPV1 messenger ribonucleic acid levels decreased – suggesting that whilst TRPV1 protein may be down-regulated during I/R in vitro, when neurones 3 Abstract innvervating the heart are associated with their cell bodies, TRPV1 expression may be increased, possibly under the control of neurotrophic factors. Together, the findings from this thesis identify a novel 12-LOX/AA/TRPV1 pathway activated and up-regulated during myocardial I/R injury, providing an endogenous damage-limiting mechanism – the targeting of which may prove useful in treating myocardial infarction or protecting against I/R injury associated with common surgical procedures including cardiac transplantation. 4 In memory of my uncle Thomas Michael Goddard (6th January 1934 – 18th October 2005) 5 ACKNOWLEDGEMENTS I would like to thank my supervisor, Professor Amrita Ahluwalia, for all the hours she has devoted to guiding me through my time as a PhD student in her laboratory; for her expertise, honesty, patience, and above all, for her endless supply of encouragement, especially at times when my enthusiasm was fading or my confidence lacking. I would also like to take the opportunity to acknowledge my school teachers Trevor Boulden, Jacky Langton and Ann Port, whose biology lessons originally inspired me to persue a biological sciences education. I am indebted to the British Heart Foundation for funding my research, and making this PhD possible. I would also like to thank the other members of Professor Ahluwalia’s group – past or present – who have helped me with various aspects of this thesis. Particular thanks go to Dr. Paul Foster (originally my secondary supervisor) and Dr. Andrew Webb, for teaching me how to use the Langendorff preparation; Dr. Ramona Scotland, for help with mouse Langendorff work; Dr. Phuong Vo, Dr. Stephanie Francis and Ms Florence Lecomte for teaching me Western blot techniques; and Dr. Cecile Cayla and Dr. Johan Duchene for teaching me PCR techniques. Thanks also go to Professor Chris Thiemermann for collaborating with the in vivo work included in this thesis, especially to Dr. Michelle McDonald who carried out all the in vivo I/R experiments on my behalf. I am very grateful to Dr. Sandro Giuliani for his generous gifts of SR 140333, MEN 11420 and SR 142801. In addition, I would like to thank Sandesh Masih for producing the graphics in Chapter 1, Dr. Natalie Lumsden for preparing and photographing heart tissue for Chapter 2, and Dr. Melissa Chan for her assistance in producing the figures in Chapters 3, 4 and 5. Lastly I would like to thank all my family and friends who have shared the highs and lows of this PhD with me. Very, very special thanks to my parents and my sister, Catherine, for your constant love and support in every possible way. I would never have managed to finish this without your help. And to my son, Oliver, thank you for all the smiles, cuddles and laughs over the past four years - this thesis is dedicated to you. 6 PUBLICATIONS The following publications have resulted from this thesis: Papers SEXTON, A.*, MCDONALD, M., CAYLA, C., THIEMERMANN, C. & AHLUWALIA, A. (2007). 12-Lipoxygenase-derived eicosanoids protect against myocardial ischemia/reperfusion injury via activation of neuronal TRPV1. FASEB J. 21, 2965-2703. Abstracts A. M. Goddard & A. Ahluwalia. Role for sensory neuropeptides in AA- induced coronary vasodilation: a potential mechanism for 12-LOX-induced cardioprotection? Winter British Pharmacological Society Meeting (2005). (Oral) Alison M. D. Sexton*, Michelle C. McDonald, Chris Thiemermann, Amrita Ahluwalia. C-fibres and the non-selective cation channel TRPV1. Experimental Biology Meeting (2006). (Poster) * former married name 7 CONTENTS DECLARATION OF OWNERSHIP 2 ABSTRACT 3 ACKNOWLEDGEMENTS 6 PUBLICATIONS 7 CONTENTS 8 INDEX OF FIGURES 14 INDEX OF TABLES 17 ABBREVIATIONS 18 CHAPTER 1: INTRODUCTION 26 1.1. General background 26 1.2. Myocardial I/R injury 31 1.2.1. Ischaemic injury 31 1.2.2. Reperfusion injury 36 1.2.3. Mechanisms of ischaemic and reperfusion injury 44 1.2.4. Protection against myocardial I/R injury 48 1.3. The PLA2/AA cascade and LOX-derived eicosanoids 51 1.4. Sensory C-fibres 57 1.5. TRPV1 65 1.5.1. TRPV1 structure, function and distribution 65 1.5.2. Modulation of TRPV1 activity 73 8 1.5.3. TRPV1 in the cardiovascular system 77 1.5.4. TRPV1 and cardioprotection 79 1.6. Aims 81 CHAPTER 2: METHODS 83 2.1. Animal preparation 83 2.1.1. Rats 83 2.1.2. Mice 83 2.2. Isolated perfused heart (Langendorff) preparation 84 2.2.1. Measurement of coronary haemodynamics in rat hearts 87 2.2.1.1. Drug administration 88 2.2.1.2. Calculation of changes in CPP 90 2.2.2. Investigation of the vasodilator activity of 12(S)-HETE and 12(S)- 90 HpETE 2.2.2.1. Determination of the role of sensory C-fibres and TRPV1 in 12(S)- 91 HpETE-induced vasodilatation 2.2.2.2. Investigation of the effect of sensory neuropeptide antagonists on 92 12(S)-HpETE-induced vasodilatation 2.2.3. 12-LOX and AA: an alternative approach to studying 12(S)-HpETE- 93 induced vasodilatation? 2.2.4. Investigation of the mechanism of 12-LOX/AA-induced coronary 95 vasodilatation 2.2.4.1. Determination of the role of sensory C-fibres and TRPV1 in 96 12-LOX/AA-induced vasodilatation 2.2.4.2. Investigation of the effect of sensory neuropeptide antagonists on 96 12-LOX/AA-induced vasodilatation 9 2.2.5. Measurement of cardiac function in rat hearts subjected to an I/R insult 97 2.2.6. Investigation of the effects of 12-LOX and AA on I/R injury 100 2.2.7. Determination of the role of sensory C-fibres in 12-LOX/AA-mediated 101 cardioprotection 2.2.8. Measurement of coronary haemodynamics in murine hearts 102 2.2.9. 12-LOX/AA-induced coronary vasodilatation in TRPV1 KO mice 103 2.3. Assessment of TRPV1 mRNA levels and protein expression 103 2.3.1. In vivo model of I/R 103 2.3.2. Sample collection 104 2.3.3. Quantitative real-time polymerase chain reaction (PCR) analysis 105 2.3.3.1. Total mRNA extraction from heart tissue (in vitro and in vivo 105 samples) 2.3.3.2. Total mRNA extraction from DRG (in vivo samples) 106 2.3.3.3. First-strand cDNA synthesis (reverse transcription, RT) 107 2.3.3.4. Optimisation of conditions for quantitative real-time PCR 110 2.3.3.4a. Conditions for conventional PCR 112 2.3.3.4b. Conditions for quantitative real-time PCR 114 2.3.3.5. Quantitative real-time PCR 117 2.3.4. Western blot 118 2.3.4.1. Sample collection 118 2.3.4.2. Preparation of tissue samples for Western blot 119 2.3.4.3. Determination of protein concentration (Bradford assay) 120 2.3.4.4. SDS polyacrylamide gel electrophoresis (SDS-PAGE) 120 2.3.4.5. Preparation of gels 121 2.3.4.6. Electrophoresis 122 10 2.3.4.7. Protein transfer 123 2.3.4.8. Incubation and detection 124 2.3.4.9. Effects of I/R injury on TRPV1 protein expression 125 2.4. Preparation of drugs 125 2.5. Sources of drugs 127 2.6. Data analysis and statistics 128 CHAPTER 3: VASODILATOR RESPONSES IN THE 133 ISOLATED RAT AND MURINE HEART 3.1. Vasodilator activity of 12(S)-HETE and 12(S)-HpETE 133 3.1.1. The role of sensory C-fibres and TRPV1 in 12(S)-HpETE-induced 137 vasodilatation 3.1.2. The effect of sensory neuropeptide antagonists on 12(S)-HpETE-induced 138 vasodilatation 3.2. 12-LOX and AA: an alternative approach to studying 12(S)-HpETE- 141 induced vasodilatation 3.3.
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