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Novel Factors Regulating Cardiac Remodeling in Experimental Models of Cardiac Hypertrophy and Failure

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Novel Factors Regulating Cardiac Remodeling in Experimental Models of Cardiac Hypertrophy and Failure D 1481 OULU 2018 D 1481 UNIVERSITY OF OULU P.O. Box 8000 FI-90014 UNIVERSITY OF OULU FINLAND ACTA UNIVERSITATIS OULUENSIS ACTA UNIVERSITATIS OULUENSIS ACTA DMEDICA Annina Kelloniemi Annina Kelloniemi University Lecturer Tuomo Glumoff NOVEL FACTORS University Lecturer Santeri Palviainen REGULATING CARDIAC Postdoctoral research fellow Sanna Taskila REMODELING IN EXPERIMENTAL MODELS Professor Olli Vuolteenaho OF CARDIAC HYPERTROPHY University Lecturer Veli-Matti Ulvinen AND FAILURE Planning Director Pertti Tikkanen Professor Jari Juga University Lecturer Anu Soikkeli Professor Olli Vuolteenaho UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE; Publications Editor Kirsti Nurkkala BIOCENTER OULU ISBN 978-952-62-2028-4 (Paperback) ISBN 978-952-62-2029-1 (PDF) ISSN 0355-3221 (Print) ISSN 1796-2234 (Online) ACTA UNIVERSITATIS OULUENSIS D Medica 1481 ANNINA KELLONIEMI NOVEL FACTORS REGULATING CARDIAC REMODELING IN EXPERIMENTAL MODELS OF CARDIAC HYPERTROPHY AND FAILURE Academic dissertation to be presented with the assent of the Doctoral Training Committee of Health and Biosciences of the University of Oulu for public defence in Auditorium F202 of the Faculty of Medicine (Aapistie 5 B), on 26 October 2018, at 12 noon UNIVERSITY OF OULU, OULU 2018 Copyright © 2018 Acta Univ. Oul. D 1481, 2018 Supervised by Professor Heikki Ruskoaho Associate Professor Jaana Rysä Reviewed by Docent Päivi Lakkisto Docent Minna Kaikkonen-Määttä ISBN 978-952-62-2028-4 (Paperback) ISBN 978-952-62-2029-1 (PDF) ISSN 0355-3221 (Printed) ISSN 1796-2234 (Online) Cover Design Raimo Ahonen JUVENES PRINT TAMPERE 2018 Kelloniemi, Annina, Novel factors regulating cardiac remodeling in experimental models of cardiac hypertrophy and failure. University of Oulu Graduate School; University of Oulu, Faculty of Medicine; University of Oulu, Biocenter Oulu Acta Univ. Oul. D 1481, 2018 University of Oulu, P.O. Box 8000, FI-90014 University of Oulu, Finland Abstract Cardiac loading induces left ventricular hypertrophy and cardiac remodeling which when prolonged, leads to heart failure, a complex syndrome affecting approximately 1-2% of the adult population of the Western world with a prevalence increasing with age. Pathological remodeling involves functional and structural changes that are associated with fetal gene expression, sarcomeric re-organization, hypertrophy of cardiomyocytes, fibrosis, inflammation, oxidative stress and impairment of metabolism. The aim of this study was to investigate the role of three novel factors during the cardiac remodeling process with different experimental models of cardiac overload. Phosphatase and actin regulator 1 (Phacr1) expression was rapidly downregulated due to myocardial infarction (MI). Adenovirus-mediated Phactr1 overexpression changed the skeletal α-actin to cardiac α-actin ratio in both healthy and infarcted rat hearts and cultured cardiomyocytes. Phactr1 could regulate the actin isoform switch via the serum response factor (SRF). The expression of transforming growth factor (TGF)- β-stimulated clone 22 (TSC-22) was rapidly induced by multiple hypertrophic stimuli and was also evident post-MI. In addition, TSC-22 could regulate collagen 3a1 expression in the heart. The expression of retinal degeneration 3-like (Rd3l) was downregulated in response to pressure overload and also downregulated post-MI. Rd3l knockout mice expressed increased myocyte hypertrophy and cardiac dysfunction in response to a transverse aortic constriction (TAC) induced pressure overload. This thesis provides novel information about Phactr1, TSC-22 and Rd3l in load-induced cardiac hypertrophy and remodeling. Collectively these studies increase our understanding of the regulatory mechanisms underlying the progression of heart failure. Keywords: cardiac hypertrophy, cardiac remodeling, gene expression, myocardial infarction Kelloniemi, Annina, Sydämen uudelleenmuovautumista säätelevät uudet tekijät sydämen hypertrofian ja vajaatoiminnan kokeellisissa malleissa. Oulun yliopiston tutkijakoulu; Oulun yliopisto, Lääketieteellinen tiedekunta; Oulun yliopisto, Biocenter Oulu Acta Univ. Oul. D 1481, 2018 Oulun yliopisto, PL 8000, 90014 Oulun yliopisto Tiivistelmä Sydämen kuormitus saa aikaan vasemman kammion liikakasvun eli hypertrofian ja sydämen uudelleenmuovautumisen, mikä pitkittyessään johtaa sydämen vajaatoimintaan. Sydämen vajaa- toiminta on monimutkainen oireyhtymä, josta länsimaissa kärsii noin 1-2 % aikuisväestöstä, ja esiintyvyys nousee iän myötä. Patologisessa uudelleenmuovautumisessa tapahtuu toiminnallisia ja rakenteellisia muutoksia, joihin liittyy muutoksia geenien ilmentymisessä, sarkomeerin uudel- leen järjestäytymistä, sydänlihassolujen koon kasvua, fibroosia, tulehdusta, oksidatiivista stres- siä ja aineenvaihdunnan huonontumista. Tämän työn tarkoituksena oli tutkia kolmen uuden tekijän roolia sydämen uudelleenmuovau- tumisessa erilaisissa kokeellisissa sydämen kuormituksen malleissa. Fosfataasin ja aktiinin sää- telijä 1:n (Phactr1) ilmentyminen väheni nopeasti infarktin seurauksena. Adenovirusvälitteinen Phactr1:n ylituotanto muutti luusto- ja sydänlihasaktiinien isomuotojen suhdetta sekä terveessä että infarktisydämessä, samoin viljellyissä sydänlihassoluissa. Phactr1 saattaa säädellä isomuo- tojen suhdetta seerumiresponsiivisen tekijän (SRF) avulla. Transformoituvan kasvutekijä β1:n stimuloima proteiini 22:n (TSC-22) ilmentyminen nousi nopeasti usean hypertrofisen stimuluk- sen seurauksena sekä infarktin jälkeen. Lisäksi TSC-22 voisi säädellä kollageeni 3a1:n ilmenty- mistä sydämessä. Retinan degeneroituvan proteiinin 3 kaltaisen tekijän (Rd3l) ilmentyminen väheni sekä painekuormituksen että infarktin seurauksena. Rd3l-poistogeenisillä hiirillä aortan ahtauman aiheuttama painekuormitus sai aikaan lisääntynyttä sydänlihassolujen hypertrofiaa ja sydämen toimintahäiriöitä. Tämä väitöskirjatutkimus tuo uutta tietoa Phactr1-, TSC-22- ja Rd3l-geeneistä kuormituksen aiheuttamassa sydämen hypertrofiassa ja uudelleenmuovautumisessa. Nämä tulokset auttavat osaltaan ymmärtämään monimutkaisia molekyylitason mekanismeja, jotka johtavat sydämen vajaatoiminnan kehittymiseen. Asasanat: geenien ilmentyminen, hypertrofia, infarkti, sydämen uudelleen- muovautuminen Acknowledgements This work was carried out at the Department of Pharmacology and Toxicology, Research Unit of Biomedicine, University of Oulu. I owe my deepest gratitude for my supervisors Professor Heikki Ruskoaho and Associate Professor Jaana Rysä. Heikki’s optimism, enthusiasm and vast knowledge of science is impressive. I am very grateful to him for giving me the possibility to do research in his dynamic research group in well-equipped environment. Jaana is acknowledged for her excellent guidance and endless encouragement. Especially I am grateful for her support in daily practical scientific matters and for always finding time to help. Jaana’s contribution has been indispensable to this project. I wish to thank Professor Emeritus Olavi Pelkonen and Professor Jukka Hakkola, the former and current heads of the department for providing an inspiring and relaxed atmosphere in which to work. I thank Docents Päivi Lakkisto and Minna Kaikkonen-Määttä for their critical review of the thesis and for their constructive comments. I also thank Ewen MacDonald for excellent revision of my English and Anna Vuolteenaho for revising the Finnish abstract. I am grateful to all my co-authors Professor Olle Melander, Professor Thomas Hedner, Professor Risto Kerkelä, Raija Soininen, Raisa Serpi, Zoltan Szabo, Juha Näpänkangas, Jani Aro, Pauli Ohukainen, Erja Mustonen, Leena Kaikkonen, Elina Koivisto, Olli Tenhunen, Margret Leosdottir and Zsolt Bagyura for their scientific contribution. I owe my gratitude to Sirpa Rutanen, Kati Lampinen, Marja Arbelius, Kaisa Penttilä, Kirsi Salo and Pirjo Korpi for their skillful assistance and guidance in the laboratory. Especially Kati’s contribution has been essential for completion of the projects. Erja Tomperi and Mirja Vahera are also acknowledged for their technical assistance with immunohistochemistry. I wish to thank the personnel at the Laboratory Animal Centre and at the Biocenter Oulu Transgenic core facility. I am also grateful for Raija Hanni, Esa Kerttula, Marja Räinä and Pirkko Viitala for taking care of all the practical matters in the department. All the past and present members of our research group are thanked for their collaboration, company and help. Alicia Jurado Acosta, Leena Kaikkonen, Elina Koivisto, Erja Mustonen, Virva Pohjolainen and Laura Vainio deserve special thanks for their joyful company during unforgettable congress trips. Pauli Ohukainen is greatly acknowledged for his invaluable friendship, support and optimism that have helped me to overcome the final obstacles of this project. I 7 warmly thank Tarja Alakoski, Jani Aro, Sini Kinnunen, Anna-Maria Kubin, Hanne Luosujärvi, Johanna Magga, Anne-Mari Moilanen, Ábel Perjés, Tuomas Peltonen, Raisa Serpi, Zoltan Szabo, Hanna Säkkinen, Olli Tenhunen, Heikki Tokola, Anna- Maria Tolonen and Maria Tölli for their excellent company in the lab, as well as during the lunch breaks. Other colleagues in Farmis are warmly acknowledged as well. I cannot express enough my gratitude to all my friends. In particular, friendship of Kristiina, Ari-Matti as well as Suvi, Sami and the other members of ”Kuukkelit” has brought joy and meaning for my life. Thank you for persuading me out of lab to enjoy outdoor activities and to hilarious social events. I owe my deepest gratitude to my parents
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