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Scleraxis Is a Mechanoresponsive Regulator of the Cardiac Myofibroblast Phenotype

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Scleraxis Is a Mechanoresponsive Regulator of the Cardiac Myofibroblast Phenotype Scleraxis is a mechanoresponsive regulator of the cardiac myofibroblast phenotype By Patricia Roche A Thesis submitted to the Faculty of Graduate Studies of The University of Manitoba In partial fulfillment of the requirements of the degree of MASTER OF SCIENCE Department of Physiology and Pathophysiology University of Manitoba Winnipeg Copyright © 2015 Patricia Roche Abstract Cardiac fibrosis is the excess deposition of myocardial extracellular matrix components, which increases tissue stiffness and heterogeneity, causing impaired diastolic/systolic function and arrhythmias, and eventually leading to heart failure and death. There are no available treatments for cardiac fibrosis. Myofibroblasts mediate fibrosis, and are characterized by hypersynthesis of collagens, decreased migration, and increased α- smooth muscle actin, which is incorporated into stress fibers, imparting contractility. Scleraxis is a transcriptional regulator of collagen-rich tissues, increased in response to the same stimuli that drive the myofibroblast phenotype, such as cyclic stretch. We show that Scleraxis mediates the conversion of cardiac fibroblasts to myofibroblasts, by increasing myofibroblast marker expression and contraction, and decreasing migration. Additionally, a proximal 1500 bp human SCLERAXIS promoter is activated by stretch and is responsive to transforming growth factor-β1. Thus, Scleraxis is a specific mechanoresponsive regulator of the myofibroblast, representing a novel target for the treatment of cardiac fibrosis. i Acknowledgements First and foremost I express my gratitude to my supervisor Dr. Michael Czubryt for the support, guidance, and encouragement he has provided throughout the course of my Master’s program, and the numerous opportunities to recognize and develop upon my strengths and overcome seemingly insurmountable obstacles. I would also like to thank the current and former members of the Czubryt lab for their assistance, expertise, and support, most especially Rushita Bagchi, Viktoriya Mozolevska, Nina Aroutiounova, Matthew Bzura, and Sasha Blant. I extend my gratitude to Dr. Ryan Cunnington, Sunil Rattan, Morvarid Kavosh, and Alison Müller for their expertise and Dr. Ian Dixon for provision of the equipment necessary to complete the collagen gel contraction and wound healing assays. Additionally, I would like to thank Dr. Jeffrey Wigle, Dr. Mark Hnatowich, Dr. Josette Northcott, Matthew Zeglinski, and David Cheung for their expertise and assistance in creating the vectors and performing Luciferase assays. I would like to thank Dr. Grant Pierce, Dr. Justin Deniset, and Thomas Hedley for their assistance in performing the cyclic stretch assays, and Drs. Todd Duhamel and Jeffrey Wigle for the generous use of their tissue culture facilities. I would also like to thank Dr. Paul Fernyhough for the generous contribution of animal tissues. I would also like to acknowledge the members of my committee, Drs. Michael Czubryt, Jeffrey Wigle, Ian Dixon, Peter Zahradka, and Darren Freed, for their invaluable feedback, advice, and insight throughout the program, as well as for challenging my memory, intelligence, and critical thinking to allow my growth as a graduate student and young scientist. I gratefully acknowledge the funding agencies that have made these experiments, and others, possible, including Research Manitoba, Canadian Institutes for Health Research, and the Heart & Stroke Foundation. I am extremely thankful for the support provided by my dear family, who have been endlessly understanding, compassionate, and generous throughout the course of my Master’s program (and beyond). Thank you to my friends, for making sure I still had fun throughout it all. Thank you to Jesse Fisher, for his continued love and support. This thesis is dedicated to my father, Hugh Roche, who has always pushed me to do better and be better, no matter how hard I push back. “Whether you think you can, or you think you can’t, you’re right.” -Henry Ford ii Table of Contents Abstract ................................................................................................................................. i Acknowledgements ............................................................................................................. ii List of Abbreviations .......................................................................................................... vi List of Tables ...................................................................................................................... ix List of Figures ..................................................................................................................... ix 1: INTRODUCTION ........................................................................................................... 1 1.1: Fibroblasts and Cardiovascular Disease .................................................................... 2 1.1.1: Response to Myocardial Injury........................................................................... 2 1.2: Extracellular Matrix of the Heart .............................................................................. 5 1.2.1: Collagens in the Cardiac Extracellular Matrix ................................................... 5 1.2.2: Non-Collagen Matrix Components .................................................................... 6 1.2.2.1: Fibronectin ................................................................................................... 8 1.2.3: Cardiac Fibroblasts and the Extracellular Matrix .................................................. 8 1.3: Migration of Cardiac Fibroblasts .............................................................................. 9 1.4: Phenoconversion of Cardiac Fibroblasts to Myofibroblasts ................................... 15 1.4.1: Regulation of Phenoconversion ........................................................................ 18 1.5: Transforming Growth Factor-β1 ............................................................................. 20 1.5.1: Canonical TGFβ Signaling ............................................................................... 22 1.5.2: Non-Canonical TGFβ Signaling ....................................................................... 23 1.5.2.1: Phosphatidylinositol 3-kinase/Akt Signaling Pathway .............................. 24 1.5.2.2: Mitogen-Activated Protein Kinase/Extracellular-Signal-Regulated Kinase Signaling Pathway .................................................................................................. 25 1.5.2.3: Rho Signaling Pathway .............................................................................. 26 1.6: Cell-Matrix Adhesions ............................................................................................ 30 1.6.1: Formation of Focal Complexes ........................................................................ 31 1.6.1.1: Signaling Pathways in Focal Complex Formation .................................... 31 1.6.2: Maturation of Focal Adhesions ........................................................................ 32 1.6.2.1: Signaling Pathways in Focal Adhesion Maturation ................................... 33 1.7: Mechanotransduction in Fibroblasts and Myofibroblasts ....................................... 33 1.7.1: Rho Signaling Pathway in Mechanotransduction ............................................. 36 1.7.2: Response to Stretch .......................................................................................... 38 1.7.2.1: Focal Adhesion Kinase in Response to Cyclic Stretch .............................. 40 iii 1.8: Myofibroblast Contraction ...................................................................................... 41 1.8.1: Stress Fibers ...................................................................................................... 41 1.8.2: Mechanisms of Myofibroblast Contraction ...................................................... 42 1.9: Scleraxis .................................................................................................................. 45 1.9.1: Basic Helix-Loop-Helix Proteins ..................................................................... 45 1.9.2: Role of Scleraxis in Development .................................................................... 46 1.9.3: Scleraxis in the Heart ........................................................................................ 47 1.9.4: Role of Scleraxis in Transforming Growth Factor-β Signaling ........................... 48 1.9.5: Response of Scleraxis to Mechanical Force ..................................................... 50 2: RATIONALE, HYPOTHESIS & OBJECTIVES ......................................................... 52 2.1: Scleraxis as a Mechanoresponsive Regulator of the Cardiac Myofibroblast .......... 52 2.1.1: Objective 1 – The Effect of Cyclic Stretch....................................................... 52 2.1.2: Objective 2 – The Effect of Scleraxis Expression ............................................ 52 2.1.3: Objective 3 – Scleraxis and Contractility ......................................................... 53 2.1.4: Objective 4 – Scleraxis and Migration ............................................................. 53 2.2: The SCLERAXIS Promoter ...................................................................................... 53 2.2.1: Objective 5 – Activation of the SCLERAXIS Promoter by TGFβ1 .................. 54 2.2.2: Objective 6 – Activation of the SCLERAXIS Promoter by Cyclic
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