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The Role of Exercise in Polychlorinated Biphenyl Induced Cardiovascular Disease

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The Role of Exercise in Polychlorinated Biphenyl Induced Cardiovascular Disease University of Kentucky UKnowledge Theses and Dissertations--Nutritional Sciences Nutritional Sciences 2014 The Role of Exercise in Polychlorinated Biphenyl Induced Cardiovascular Disease Margaret O'Bryan Murphy University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Murphy, Margaret O'Bryan, "The Role of Exercise in Polychlorinated Biphenyl Induced Cardiovascular Disease" (2014). Theses and Dissertations--Nutritional Sciences. 13. https://uknowledge.uky.edu/nutrisci_etds/13 This Doctoral Dissertation is brought to you for free and open access by the Nutritional Sciences at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Nutritional Sciences by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Margaret O'Bryan Murphy, Student Dr. Bernhard Hennig, Major Professor Dr. Howard Glauert, Director of Graduate Studies THE ROLE OF EXERCISE IN POLYCHLORINATED BIPHENYL INDUCED CARDIOVASCULAR DISEASE ___________________________ DISSERTATION ___________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Margaret O’Bryan Murphy Lexington, Kentucky Director: Dr. Bernhard Hennig, Professor of Nutrition and Toxicology Lexington, Kentucky 2014 Copyright © Margaret O’Bryan Murphy 2014 ABSTRACT OF DISSERTATION THE ROLE OF EXERCISE IN POLYCHLORINATED BIPHENYL-INDUCED CARDIOVASCULAR DISEASE Cardiovascular disease remains the leading cause of death in Western societies. Endothelial dysfunction is one of the initiating steps in the development of atherosclerosis. While there is a strong correlation with a person’s genetics, lifestyle factors including smoking, physical activity, and diet can significantly increase a person’s susceptibility to the development of atherosclerosis. In addition to these lifestyle factors, there is a strong body of evidence linking exposure to environmental pollutants including persistent organic pollutants such as polychlorinated biphenyls to increased cardiovascular disease and mortality. It has been well-established that exercise protects against cardiovascular disease, but whether exercise can modulate PCB- induced cardiovascular inflammation and dysfunction is unknown. To investigate the effects of exercise on PCB-induced cardiovascular disease, two murine models of atherosclerosis, the ApoE-/- and the LDLr-/- mouse were utilized. Risk factors for cardiovascular disease including adiposity, glucose intolerance, hyperlipidemia, hypertension, oxidative stress, and inflammation, were assessed in these two models as well as mean atherosclerotic lesion size. Exercise positively modulates several risk factors associated with cardiovascular disease including hypertension, hyperlipidemia, adiposity and obesity, systemic levels of oxidative stress, inflammation, and glucose tolerance. Exercise significantly reduced mean lesion size in vehicle-treated animals. To assess the mechanism of protection of exercise in chapter 4, vascular reactivity studies were performed to measure endothelial function after exposure to PCB 77. Exercise prevented PCB-impaired endothelial function implicating the role of superoxide as a cause of impairment. Exercise upregulated phase II antioxidant enzymes. The work in this dissertation demonstrates several protective properties of exercise against PCB-induced cardiovascular disease; however, additional studies are needed to determine if exercise enhances metabolism and excretion of these environmental pollutants. KEYWORDS: cardiovascular disease (CVD); Polychlorinated biphenyls (PCBs); exercise, oxidative stress, endothelium dysfunction Margaret O’Bryan Murphy Student’s Signature May 8, 2014 Date THE ROLE OF EXERCISE IN POLYCHLORINATED BIPHENYL INDUCED CARDIOVASCULAR DISEASE By Margaret O’Bryan Murphy Dr. Bernhard Hennig Director of Dissertation Dr. Howard Glauert Director of Graduate Studies May 8, 2014 Date In dedication to Margaret O’Bryan Fitts Acknowledgements I would like to acknowledge several people who assisted me in the completion of this dissertation. First, I would like to thank my mentor, Dr. Bernhard Hennig who offered me a position in his laboratory after serving as his teaching assistant. Without your guidance, none of this could have occurred. Thank you helping me grow not only in my career as a scientist on a personal level as well. To my other committee members, thank you for your assistance. Dr. Esser, thank you for being a strong female scientist and true role model. Additionally, thank you for collaborating with us by providing running wheel cages. To Dr. Pearson, thank you for your continued support and enthusiasm about my project and growth as a scientist. To Dr. Cassis, thank you for encouragement and insights into assisting this project along. Your expertise has truly been appreciated in developing dosing regimens as well as the appropriate mouse model to conduct these experiments. Dr. Li, thank you for your critical thought and advice for continuing my work. Dr. Newman, thank you for serving as an outside examiner. To my fellow labmates, current and previous, I thank you for your continued support, kindness, and advice during this time. Michael Petriello, your academic input has been thoroughly appreciated and necessary. Dr. Zuzana Makjova and Dr. Sung Gu Han, your expertise and training has been invaluable. Katryn Eske, thank you for your kindness and assistance in animal work. To Brad Newsome, thank you for your editing expertise and friendship. The laboratory of Alan Daugherty allowed me to perform and refine many experiments within this dissertation. Jess, thank you for setting up the contractility apparatus and providing me detailed training to conduce these ex vivo experiments. Deborah, your training on aortic root sectioning has been very helpful, you are truly a iii master. I am eternally grateful for the day that you and Jess helped me handle a mouse without fear. Anju, thank you for blood pressure training and animal assistance. I would also like to acknowledge Dr. Morris and Manjula Sunkara for their assistance and availability to analyze PCB 77, its metabolites, and F2-isoprostanes. To my family and friends, thank you for your continued support, encouragement and love during this time. I am truly grateful for your love and kindness. To Tom Gawriluk, thank you for your continued passion for science. I dedicate this work to my grandmother and namesake, Margaret O’Bryan Fitts, who would have been a brilliant scientist had she lived in a different generation when women had more opportunities. iv Table of Contents ACKNOWLEDGEMENTS ........................................................................................................................... III TABLE OF CONTENTS ................................................................................................................................ V LIST OF FIGURES .................................................................................................................................... VIII LIST OF TABLES ........................................................................................................................................ IX CHAPTER 1: INTRODUCTION .................................................................................................................... 1 1.1 CARDIOVASCULAR DISEASES AND PATHOLOGY OF ATHEROSCLEROSIS ................................................................... 1 1.1.1 The role of endothelium in atherosclerosis .................................................................................... 3 1.1.2. Mechanisms of Atherosclerosis-Shear Stress and Physical Inactivity ........................................... 3 1.2. AN OVERVIEW OF PCBS ............................................................................................................................
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