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Epigenetic Regulation of Genes Involved in Vascular Dysfunction in Preeclamptic Women

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Epigenetic Regulation of Genes Involved in Vascular Dysfunction in Preeclamptic Women Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 EPIGENETIC REGULATION OF GENES INVOLVED IN VASCULAR DYSFUNCTION IN PREECLAMPTIC WOMEN Ahmad Mousa Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2645 This Dissertation is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Ahmad A. Mousa, 2012 All Rights Reserved EPIGENETIC REGULATION OF GENES INVOLVED IN VASCULAR DYSFUNCTION IN PREECLAMPTIC WOMEN A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. by Ahmad A. Mousa Bachelor of Dental Surgery, Jordan University of Science and Technology, 2005 Advisor: Scott W. Walsh, Ph.D. Professor Department of Obstetrics & Gynecology and Physiology and Biophysics Virginia Commonwealth University Richmond, Virginia January, 2012 ii ACKNOWLEDGEMENT I would like to express my sincere gratitude to my Lord (Allah), who gave me the opportunity and the blessings to explore a minute aspect of his amazing creation and to realize how limited we are in front of his greatness and ability. Without his help and mercy I would not be able to do anything good in my life. I would like next to thank my Mentor Dr. Walsh for providing me with the opportunity to perform research in his lab and be part of his research group. Dr. Walsh largely contributed to my success in my Ph.D. career through his patience, kindness and continuous emotional and intellectual support. I am very thankful for my Ph.D. committee members for their kindness and support. I thank Dr. Strauss for his continuous help and advice, Dr. Gerk for letting me use his lab equipment, Dr. Pittman for providing me with animal tissue whenever I needed, and Dr. Karnam for the valuable technical support I received from him and his lab members. My thanks to all the staff members of the Department of Physiology and Biophysics and the School of Graduate studies. My best regards to my labmates and friends whom I always found whenever I needed help. They were like a family for me while being away from my home. I would like to specially thank our lab specialist Sonya Washington and my friends Khalid Abu Zaid, Mehrubon Safaraliev, Alae Yaseen and Nibras Aldolimi for all of what they did for me. I would like to thank my father, mother, brothers, sisters, father in law, mother in law and brothers and sisters in law for all the support, prayers and blessings they provided to me. Without these people I won’t be able to reach at this stage. I would like to thank Jordan University of Science and Technology for the finical support during my studies. My sincere recognition for Dr. Said khatib who opened my eyes for this opportunity and for all his help and guidance. iii Last, but not the least, I would like to express my deep and heartfelt thanks to my beloved wife, Dr. Ikhlas D. Darkhalil, for all the sacrifice she made for me. She has been, always, my pillar, my joy and my guiding light. Her support and encouragement in the end was what made this dissertation possible. I pray that we will stay together for the rest of our life as a happy family. This has been a great experience, filled with tremendous memories both good and bad. I am convinced that the training and knowledge I have received will help me prosper in my professional life. And again before I finish, I would like to say Thanks God, for helping me finish my Ph.D. and reach this far. iv TABLE OF CONTENT ACKNOWLEDGEMENT ........................................................................................................................ III TABLE OF CONTENT ............................................................................................................................. V LIST OF FIGURES ................................................................................................................................ XII LIST OF ABBRIVIATIONS ................................................................................................................. XIV ABSTRACT .......................................................................................................................................... XVII CHAPTER 1: GENERAL INTRODUCTION ......................................................................................... 1 A. DEFINITION OF PREECLAMPSIA, ITS CLINICAL SYMPTOMS AND COMPLICATIONS ................................ 1 B. EPIDEMIOLOGY ..................................................................................................................................... 3 C. PREVENTION AND TREATMENT ............................................................................................................. 4 D. PATHOPHYSIOLOGY OF PREECLAMPSIA ............................................................................................... 4 1. Poor placentation in preeclampsia ................................................................................................... 5 2. Neutrophil activation in preeclampsia .............................................................................................. 6 3. Endothelial Dysfunction .................................................................................................................... 7 4. Oxidative stress ................................................................................................................................. 9 5. Thromboxane / prostacyclin imbalance .......................................................................................... 11 E. INFLAMMATION AND PREECLAMPSIA ................................................................................................. 13 F. EPIGENETICS AND DNA METHYLATION ............................................................................................. 14 G. EPIGENETICS AND PREECLAMPSIA ...................................................................................................... 18 H. THROMBOXANE SYNTHASE ................................................................................................................ 19 I. MATRIX METALLOPROTEINASES .......................................................................................................... 20 J. MATRIX METALLOPROTEINASE-1 ........................................................................................................ 21 v K. SPECIFIC AIMS .................................................................................................................................... 22 1. Specific Aim 1 .................................................................................................................................. 22 2. Specific Aim 2 .................................................................................................................................. 23 3. Specific Aim 3 .................................................................................................................................. 23 L. SIGNIFICANCE OF THIS RESEARCH ...................................................................................................... 24 CHAPTER 2: MATERIALS AND METHODS .................................................................................... 25 A. STUDY SUBJECTS ................................................................................................................................ 25 B. VESSEL DISSECTION ............................................................................................................................ 25 C. VASCULAR SMOOTH MUSCLE CELL ISOLATION AND CELL CULTURE ................................................. 27 D. HL-60 CELLS ...................................................................................................................................... 28 E. TREATMENTS OF CELL CULTURES ....................................................................................................... 28 1. Control ............................................................................................................................................ 28 2. Neutrophils ...................................................................................................................................... 28 3. ROS ................................................................................................................................................. 30 4. Tumor necrosis factor α (TNFα) ..................................................................................................... 31 5. 5-Aza-2-deoxycytidine (5-Aza) ........................................................................................................ 31 6. Phorbol 12-myristate 13-acetate (PMA) ......................................................................................... 31 7. Linoleic acid .................................................................................................................................... 32 F. CELL COLLECTION .............................................................................................................................. 32 G. IMMUNOHISTOCHEMISTRY ................................................................................................................
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