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Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches

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Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches Cigarette Smoking-Induced Endothelial Dysfunction: Molecular Mechanisms and Therapeutic Approaches DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Tamer M. Abdelghany Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2013 Dissertation Committee: Dr. Jay L. Zweier, MD, Advisor Dr. Arthur Strauch III, PhD Dr. Amal Amer, MD PhD Copyright by Tamer M. Abdelghany 2013 Abstract Cigarette smoking (CS) remains the single largest preventable cause of death. Worldwide, smoking causes more than five million deaths annually and, according to the current trends, smoking may cause up to 10 million annual deaths by 2030. In the U.S. alone, approximately half a million adults die from smoking-related illnesses each year which represents ~ 19% of all deaths in the U.S., and among them 50,000 are killed due to exposure to secondhand smoke (SHS). Smoking is a major risk factor for cardiovascular disease (CVD). The crucial event of The CVD is the endothelial dysfunction (ED). Despite of the vast number of studies conducted to address this significant health problem, the exact mechanism by which CS induces ED is not fully understood. The ultimate goal of this thesis; therefore, is to study the mechanisms by which CS induces ED, aiming at the development of new therapeutic strategies that can be used in protection and/or reversal of CS-induced ED. In the first part of this study, we developed a well-characterized animal model for chronic secondhand smoke exposure (SHSE) to study the onset and severity of the disease. In this model, SHSE impaired endothelium-dependent relaxation and triggered persistent hypertension in a time-dependent manner. This impairment was accompanied .- by over-production of superoxide (O2 ) through activation of NADPH oxidase and endothelial nitric oxide synthase (eNOS) uncoupling. Moreover, SHSE led to a decrease in eNOS expression and phosphorylation. ii In the second part of this study we used a cell model for CS-exposure to investigate the mechanism of CS-induced eNOS uncoupling. Exposure of bovine aortic endothelial cells (BAECs) to cigarette smoke extract (CSE) resulted in a significant .- decrease in nitric oxide (NO) production with concomitant increase in O2 generation as a result of BH4 depletion and eNOS uncoupling. Moreover, CSE exposure led to a decrease in GTPCH and eNOS protein expression and eNOS phosphorylation level at ser 1179. More importantly, exposure of BAECs to CSE increased the level of ubiquitinylated protein and increased 26S proteasomal activity. Inhibition of the 26S proteasome partially prevented CSE-induced reduction of Tetrahydrobiopterin (BH4), total biopterin, Guanisin tri phosphate cyclohydrolase 1 (GTPCH) level, eNOS level, and increased NO production following CSE exposure, indicating a central role of the proteasome in CSE- induced eNOS dysfunction. Finally, we examined the existence and role of eNOS S-glutathionylation in CS- .- induced ED. Exposure of BAECs to CSE led to an increase in O2 generation and depletion of cellular reduced glutathione. More importantly, S- glutathionylation of total cellular proteins and eNOS was significantly higher in CSE-exposed cells and tissue homogenates obtained from rat aortas that were exposed to CSE. Incubation with Dithiothreitol (DTT) enhanced eNOS function and decreased eNOS S-glutathionylation .- in rat aorta, and decreased O2 generation through reversal of eNOS S-glutathionylation in CSE-exposed cells. In conclusion, the results from this thesis work provide an important insight toward better understanding of the pathogenesis of CS-induced ED. Furthermore, we iii explored a new mechanism that should be targeted as a therapeutic option for treatment and prevention of CS-induced ED. iv DEDICATED TO MY MOTHER AND THE SOUL OF MY FATHER v Acknowledgments I would like to express my appreciation to the people who have played a valuable role in completion of my graduate studies. First and foremost, I would like to thank my advisor Dr. Jay Zweier, whose constant support and guidance helped me during my PhD training. The knowledge that I have gained from him while working on this dissertation and throughout my graduate career has been truly appreciated and will not be forgotten. I hope that we will continue to collaborate on future research endeavors throughout my academic career. I am also thankful to my advisory committee members Dr. Arthur Strauch, Dr. Robert Snapka, and Dr. Amal Amer for their guidance during my graduate study. I would like to thank Dr. Mohamed El-Mahdy for his constant support, expertise, guidance, and patience throughout my PhD training. He has been a great group leader and taught me much about science and other important aspects of life. I am grateful to my colleagues in The Davis Heart and Lung Research Institute. I owe a special thanks to Craig Hemann for his technical and scientific assistance. My sincerest gratitude goes out to my mother and father. Without their support none of this would have been possible. They have been a constant source of support, vi wisdom and inspiration. Their effort and sacrifice throughout my entire education mean a lot to me. I am very grateful to my wife and kids. I especially appreciate the support and patience of my wife. Since we have been married, she has been extremely understanding and supportive of my work and a constant source of encouragement. My sincerest gratitude goes out to my home country Egypt and the Egyptian Mission's Sector at the Ministry of Higher Education for the financial support during my stay in the USA. I am very grateful to my colleagues and professors at my home institution, Al- Azhar College of Pharmacy, Cairo, Egypt. I would also like to thank Dr. Ahmed Esmat and Raed Ismail for their help in my research work and for their camaraderie. I have enjoyed my time in the Graduate School at the Ohio State University with all its ups and downs and appreciate the great opportunities that it has provided. If there is anyone else who did not receive an acknowledgement, please know that it was not intentional. I have valued you in my life during this undertaking and have appreciated everything that you have done for me. vii Vita Jan 1st 1978 ................................................................ Born in Behera Egypt 2001 ............................................................................ B.S. Pharmacy, Al-Azhar University 2003 ............................................................................ Graduate Teaching Associate, Department of Pharmacology, Al- Azhar University 2009 to present ........................................................... Graduate Research Associate, MCDB, The Ohio State University Publications 1. Li, H.T., C. Hemann, T.M. Abdelghany, M.A. El-Mahdy, and J.L. Zweier, Characterization of the Mechanism and Magnitude of Cytoglobin-mediated Nitrite Reduction and Nitric Oxide Generation under Anaerobic Conditions. Journal of Biological Chemistry, 2012. 287(43): p. 36623-36633. 2. Caia, G.L., O.V. Efimova, M. Velayutham, M.A. El-Mahdy, T.M. Abdelghany, E. Kesselring, S. Petryakov, Z.Q. Sun, A. Samouilov, and J.L. Zweier, Organ specific mapping of in vivo redox state in control and cigarette smoke-exposed mice using EPR/NMR co-imaging. Journal of Magnetic Resonance, 2012. 216: p. 21-27. viii Meeting abstracts 1. Abdelghany, T.M., M.M. El-Mahdy, and J.L. Zweier, Chronic Cigarette Smoke Exposure Impairs Vascular Endothelial Function With Reactive Oxygen Species Formation and Alterations in NO Synthase. Faseb Journal, 2011. 25. 2. Zweier, J.L., A.K. Tewari, M.A. El-Mahdy, T.M. Abdelghany, C. Hemann, and G.A. El-Sherbiny, Potential Proteomic Biomarkers of Secondhand Smoking- Induced Cardiovascular Disease. Faseb Journal, 2012. 26. 3. El-Mahdy, M.A., T.M. Abdelghany, C. Hemann, S. Varadharaj, A. Esmat, G.A. El-Sherbiny, and J.L. Zweier, Involvement of the Endothelial Nitric Oxide Pathway and Leukocyte Infiltration in Secondhand Smoke Exposure-Induced Vascular Endothelial Dysfunction and Hypertension. Faseb Journal, 2012. 26. Fields of Study Major Field: Molecular, Cellular and Developmental Biology Emphasis: Cardiovascular Pharmacology and Toxicology ix Table of Contents Abstract ............................................................................................................................... ii Acknowledgments.............................................................................................................. vi Vita ................................................................................................................................... viii Publications ...................................................................................................................... viii Table of Contents ................................................................................................................ x List of Tables ................................................................................................................. xviii List of Figures .................................................................................................................. xix List of abbreviations ....................................................................................................... xxii Chapter 1: Introduction ....................................................................................................... 1 1.1 General Introduction
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