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The Role of P66shca-TLR9 Signaling in Myocardial Remodeling and Innate Immune Responses

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The Role of P66shca-TLR9 Signaling in Myocardial Remodeling and Innate Immune Responses The role of p66ShcA-TLR9 signaling in myocardial remodeling and innate immune responses Thesis for the degree of Philosophiae Doctor (Ph.D.) Anton Baysa, M.D. Division of Physiology Department of Molecular Medicine Institute of Basic Medical Science Faculty of Medicine University of Oslo 2020 © Anton Baysa, 2020 Series of dissertations submitted to the Faculty of Medicine, University of Oslo ISBN 978-82-8377-746-8 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo. Table of Contents Acknowledgements ............................................................................................... 1 List of included papers .......................................................................................... 3 Selected abbreviations........................................................................................... 4 General introduction ............................................................................................. 6 Clinical perspectives .............................................................................................................. 6 Ischemic heart disease: Global and national status ........................................................... 6 Ischemic heart disease: Emerging trends and therapy limitations .................................... 6 Ischemic heart disease: Anti-inflammatory treatment ........................................................ 7 Theoretical background .......................................................................................................... 7 Myocardial healing post-infarction: role of inflammation................................................. 7 Innate immunity: The danger theory .................................................................................. 8 Innate immunity: TLR9 pathway ........................................................................................ 8 Innate immunity: Clinical significance of the TLR9 pathway ............................................ 9 Innate immunity: TLR9 signaling and endogenous mitochondrial DNA in inflammation and ischemic heart disease ................................................................................................. 9 The ShcA gene: a regulator of heart development, metabolism, and structural integrity . 9 The p66ShcA adaptor protein: metabolism accelerator and a positive regulator of oxidative stress ................................................................................................................. 10 The p66shcA isoform: at the crossroads of myocardial ischemia, wound healing, and innate immunity ................................................................................................................ 11 Circulating extracellular DNA: origins, forms, and functions ......................................... 11 Clinical significance of extracellular DNA ...................................................................... 12 Extracellular mtDNA as a DAMP .................................................................................... 12 Role of DNA transporters in ischemic heart disease ........................................................ 13 Aims of the study ................................................................................................ 14 Methodological considerations ........................................................................... 15 Patients ................................................................................................................................. 15 Mice ...................................................................................................................................... 17 In vivo model of myocardial infarction ............................................................................ 19 Echocardiography ............................................................................................................ 20 Cell experiments ................................................................................................................... 20 Molecular biology techniques .............................................................................................. 21 Histology and immunohistochemistry .............................................................................. 21 Western blotting ................................................................................................................ 21 Co-immunoprecipitation and DuoLink assay ................................................................... 21 Summary of results ............................................................................................. 23 Paper I .................................................................................................................................. 23 Paper II ................................................................................................................................. 24 Paper III ................................................................................................................................ 25 General discussion .............................................................................................. 27 ShcA and TLR9 expression in the natural course of myocardial infarction ........................ 27 ShcA isoforms ................................................................................................................... 27 TLR9 pathway ................................................................................................................... 28 Myocardial remodeling and TLR9 pathway in p66ShcA knockout mice. ........................... 29 p66ShcA deletion improves myocardial healing post-infarction. .................................... 29 p66ShcA is necessary for TLR9 induction after myocardial ischemia. ............................ 30 p66ShcA is a positive regulator of TLR9 signaling .......................................................... 31 Extracellular mtDNA in the circulation during open heart surgery with extracorporeal circulation. ............................................................................................................................ 31 Main conclusions and some clinical perspectives .............................................. 34 Future research opportunities .............................................................................. 35 List of references ................................................................................................. 37 Other publications during doctoral period .......................................................... 55 Papers I - III ........................................................................................................ 57 To my family Acknowledgements This study started as the guest research project at the Institute for Experimental Medical Research (UiO) in 2009 and finished as a Ph.D. project at the Department of Physiology, University of Oslo (UiO) in 2015. There I have met many fantastic people whose openness, enthusiasm, and disposition toward risky investments made this work possible. I will first greatly acknowledge Professor Jarle Vaage for inviting me to UiO and being my permanent co-supervisor. Thank you for invaluable help and for sharing your realistic optimism during all these exciting and challenging years. I am especially thankful for introducing me to Professor Guro Valen. Professor Guro Valen was a bright and inspiring supervisor under whose guidance we charted the blueprint of this work. She passed away in September 2014. I see no better way to express gratitude to her than being an active researcher. Professor Kåre-Olav Stensløkken has navigated me through the most challenging part of Ph.D., the final one. Thank you for the wise combination of understanding, proactive motivation, and especially for your patience! The triumvirate of Guro, Jarle, and Kåre-Olav fostered a unique working environment – our research group was always international, open, inclusive, and creative. It is my pleasure to name my colleagues from whom I have learned a lot: Arkady Rutkovsky, Lars Henrik Mariero, Marte Bliksøen, Apple Lei, and Fred Haugen were those with whom I have worked most with. Many thanks to doctor Rutkovsky for informal and all-purpose guidance during my first years in Norway. My special thanks to Torun Flatebø for numerous Westerns and PCRs you run for me. I would also like to give a tribute to all my previous colleagues: Gabor Gzibik, Arno Russalepp, Dusan Bilbija, Bushra Ishak, Lars Petter Radich, Xueping Wu, Mohsen Foadoddini, and Julia Sagave. Furthermore, I am also grateful to the new group members for their positive input: May-Kristin Torp, Arseni Zabirnyk, Maria Bogdanova, and Christina Heiestad. Collaboration with the University of Padova, Italy and European Oncology University in Milano, Italy was crucial for this work. I am grateful to Professor Fabio Di Lisa, Professor Marco Giorgio, Professor Marco Mongillo, doctor Andrea Carpi, doctor Tania Zaglia, and Marica Campensan. I will always remember the time I have spent working at your laboratory and your hospitality in the beautiful city of Padova. Professor Anna Kostareva, and Drs. Michel Galagudza, Anton Fedorov, and Kirill Kondratov from Almazov National Medical Research Centre, St. Petersburg, Russia were central for the clinical part of this work.
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