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Pharmacological Activation of Pro-Survival Pathways As a Strategy for Improving Donor Heart Preservation

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Pharmacological Activation of Pro-Survival Pathways As a Strategy for Improving Donor Heart Preservation Pharmacological Activation of Pro-survival Pathways as a Strategy for Improving Donor Heart Preservation Jair Chau Kwan Transplant Programme, Victor Chang Cardiac Research Institute Department of Clinical Pharmacology & Toxicology and Heart Lung Transplant Unit, St. Vincent’s Hospital Sydney And Faculty of Medicine, The University of New South Wales, Sydney, Australia This thesis is submitted in fulfilment of the requirements for the degree of Doctor of Philosophy 2009 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Kwan First name: Jair Chau Other name/s: N.A. Abbreviation for degree as given in the University calendar: PhD School: Clinical School of Medicine, St. Vincent’s Hospital Faculty: Medicine Title: Pharmacological activation of pro-survival pathways as a strategy for improving donor heart preservation Abstract 350 words maximum: (PLEASE TYPE) Despite the development and use of specialised cardiac preservation solutions, the quality of the donor heart may still be compromised by its obligatory exposure to periods of ischaemia (both cold and warm) followed by reperfusion upon reintroduction of the recipient circulation. This is reflected in Transplant Registry data showing increased primary allograft failure as a function of increasing ischaemic time. The research described in this thesis is designed to further the understanding of the mechanisms by which the donor heart may be adapted to these prolonged periods of ischaemia and reperfusion by the activation of endogenous pro-survival signalling pathways by the addition of pharmacological agents to Celsior, a clinical preservation solution. Studies were conducted in an isolated working rat heart model of donor heart preservation. The first study investigated the cardioprotective effects of a novel inhibitor of poly(ADP-ribose) polymerase 1, INO-1153. Maximum protective effect (after a 6 hour storage period) was observed when the PARP inhibitor was administered prior to cardiac arrest and storage and when the agent was added to the Celsior cardioplegic / storage solution. This protective affect was associated with activation of the Akt signalling pathway and could be prevented by inhibition of Akt phosphorylation and activation. The second study examined functional protection and pro-survival signalling pathway activation in hearts arrested and stored for 6 hours in Celsior supplemented with glyceryl trinitrate (an exogenous source of nitric oxide) and Cariporide (an inhibitor of sodium hydrogen exchange). Here, cardiac protection was accompanied by activation of the ERK 1/2 pro-survival pathway as well as a decrease in apoptosis. The third study examined the cardioprotective effect of supplementation of Celsior with all three agents after an extended (10 hour) period of hypothermic storage. Significant recovery of function was only observed in the triply supplemented hearts, being accompanied by activation of both the Akt and ERK pathways. These studies demonstrate for the first time the feasibility of recruitment of endogenous pro-survival pathways as an approach to increasing the post-storage function of the donor heart. Importantly, for the logistics of clinical transplantation, these pathways can be recruited by addition of appropriate pharmacological agents to the arresting and storage solution. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...……… Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed - Date - AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed - Date - ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project’s design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed - Date - - ii - ACKNOWLEDGEMENTS Firstly, my sincere thanks to Dr. Mark Hicks for the guidance, advice, continual inspiration and excellence on the path to research. With Dr. Hicks as my ever inspiring supervisor, mentor and friend, I am humbled by his outstanding knowledge, infectious enthusiasm and academic ability which are formidable and yet he carries them with ease and charm. I thank him for his selfless and unrelenting support to share his wisdom as well as his tireless and meticulous efforts on the publications, published abstracts, seminar talks and valuable comments on the draft versions of this thesis arising from this body of work. My sincere thanks to my co-supervisor, Professor Peter Macdonald, for welcoming me into the laboratory, introducing me to the clinical arena of cardiology and giving me the opportunity to work on this critical area of cardiac transplantation. His constant encouragements, discussions and graciousness to share his wealth of knowledge have enabled me to benefit immensely in the production of this thesis. I am very grateful for his guidance and contributions towards my findings established in this body of work. My special thanks also to Dr. Ling Gao. Throughout my research undertaken for this Ph.D. thesis her tireless help and guidance has been a key determinant to my success in mastering the animal model and has - iii - generated many insights into further understanding and improvement in organ preservation and transplantation. My special thanks to fellow colleagues Dr. Alfred Hing, Dr. Alasdair Watson, Dr. Andrew Jabbour and Jireh Tsun all of whom I have enjoyed stimulated discussions and are fun to work with. I would like to acknowledge and thank Professor Jacob George, Professor Geoffrey Farrell, and Dr. Roslyn London for their invaluable guidance, support and sharing the many aspects of clinical gastroenterology and hepatology at Westmead Hospital in Sydney which provided the catalyst for me to undertake a path in medical research. My thanks and gratitude to the Victor Chang Cardiac Research Institute, National Heart Foundation, Gastroenterology Society of Australia for their funding and support of this project. To my father Cheng Fai, mother Set Lan, and sisters Cailyn and Cai Nan, to whom this work is dedicated. My deepest thanks and appreciation for their endless love, support, encouragements and sacrifices they have made over these years. Finally, to my wife May Ling. Her endless love, care, encouragement, warmth, support and believing in me is what I cherish everyday. I especially dedicate the scientific endeavour in this thesis to her. - iv - ABSTRACT Despite the development and use of specialised cardiac preservation solutions, the quality of the donor heart may still be compromised by its obligatory exposure to periods of ischaemia (both cold
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