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Purification and Characterization of Blood Aspirin Hydrolases PURIFICATION AND CHARACTERIZATION OF BLOOD ASPIRIN HYDROLASES by Gang Zhou A dissertation submitted to faculty of The Cleveland State University in partial fulfillment of requirements for the degree of DOCTOR OF PHILOSOPHY IN CLINICAL/BIOANALYTICAL CHEMISTRY Department of Chemistry Cleveland State University April 2012 © Copyright by Gang Zhou 2012 All Rights Reserved This dissertation has been approved for the Department of Chemistry and for the College of Graduate Studies of Clevelnd State University By _________________________________________Date_________________ Dr. Thomas McIntyre, Dept. of Cell Biology/Cleveland Clinic, LRI Major Advisor, Advisory Committee Chair _________________________________________Date_________________ Dr. Martha Cathcart, Dept. of Cell Biology/Cleveland Clinic, LRI Advisory Committee Member _________________________________________Date_________________ Dr. Donald Jacobsen, Dept. of Cell Biology/Cleveland Clinic, LRI Advisory Committee Member _________________________________________Date_________________ Dr. Jun Qin, Dept. of Molecular Cardiology/Cleveland Clinic, LRI Advisory Committee Member _________________________________________Date_________________ Dr. Xue-Long Sun, Dept. of Chemistry/Cleveland State University Advisory Committee Member _________________________________________Date_________________ Dr. Crystal Weyman, Dept. of BGES/Cleveland State University Advisory Committee Member ACKNOWLEDGMENTS First I would like to thank Dr. Thomas McIntyre for giving me the opportunity to work in his group and working on such an interesting thesis project. Dr. Thomas McIntyre is a great scientist. His feedback and input were vital for this shy foreign graduate student to gain appreciation and confidence in the scientific process, and my ability to use it to ask and answer relevant and important questions and to survive my Ph.D.. Also, Dr. Thomas McIntyre’s quick wit and sense of humor made working in the lab very enjoyable. Without the guidance, patience, and encouragement from him, I cannot complete this project in four years. I wish to acknowledge the contribution of many people to the development of this thesis research project and my scientific abilities. I would like to thank all members of McIntyre Lab. I especially thank Dr. Gopal Marathe for training me techniques and early involvement in this project, and lots of help on research. I thank Dr. Stanley Hazen for providing serum samples and Dr. Hooman Allayee for genome- wide data analysis. Also I thank Dr. Oksana Lockridge for providing BChE null plasma. I thank Mark Calabro and Erin Brady for plasma and erythrocytes isolation and materials ordering. I thank Dr. Thomas Tallant for providing FPLC support. I also thank Dr. Belinda Willard for mass spectrometry. I also want to thank all committee members for valuable advice and encourage. This project cannot be done without their efforts. I thank Dr. Martha Cathcart for her scientific and circumspect guidance, which made me learn more about science; thank Dr. Donald Jacobsen for his suggestions and encouragement; thank Dr. Jun Qin for his kind advice; thank Dr. Xue-long Sun for his valuable guidance and encouragement; thank Dr. Crystal Weyman for her encouragement, instruction, and enlightening in my Ph.D. study. Finally, I wish to thank my family for their love and support. I thank my parents for everything in my life and appreciate my wife’s company and support and selfless contribution to this project. Without their understanding and support this project cannot be done. PURIFICATION AND CHARACTERIZATION OF BLOOD ASPIRIN HYDROLASE GANG ZHOU ABSTRACT Aspirin prophylaxis suppresses major adverse cardiovascular events, but its turnover in blood is rapid, which limits its inhibitory effects on platelet cyclooxygenase and thrombosis. Inter-individual variability of platelet responses to aspirin clinically presents as treatment failure, and this increasing clinical phenomenon is frequently named aspirin “resistance”. However, the molecular mechanisms behind this are unclear. Blood aspirin hydrolases are believed to control aspirin survival in vivo, but the identity of the circulating enzyme(s) that hydrolyzes aspirin remains unknown. In this thesis, blood aspirin hydrolases were identified and characterized. The relationship between blood aspirin hydrolases and aspirin efficacy was investigated. RP-HPLC analysis of the product salicylic acid with an internal standard showed plasma hydrolysis of aspirin varied 12-fold variation among 2,275 individuals. Genome-wide association analysis using serum aspirin hydrolytic activity from 2,275 individuals showed a genetic component to aspirin hydrolytic variation, and that only BChE significantly associated to aspirin variation. However, plasma from an vi individual with an inactivating point mutation in BChE effectively hydrolyzed aspirin. A non-BChE aspirin hydrolase was found in plasma, which can be distinguished from BChE by procainamide and oxidized ATP. Erythrocyte aspirin hydrolase was purified by 1400-fold and type I PAF acetylhydrolase was identified as a candidate aspirinase by mass spectrometry. Recombinant PAFAH1B2 hydrolyzed aspirin and aspirin was effectively hydrolyzed in cells ectopically expressing PAFAH1B2 and PAFAH1B3. Type I PAFAH also accounts for non-BChE plasma aspirin hydrolytic activity. Both plasma and erythrocytes were found modulated aspirin efficacy significantly, which varied by aspirin hydrolytic activity variation. I hope my work in this thesis will help to understand aspirin “resistance” and shed light on personalized medicine of aspirin. vii Table of Contents ABSTRACT ................................................................................................................. vi LIST OF FIGURES ........................................................................................................x LIST OF ABBREVIATIONS ........................................................................................ xii CHAPTER I .................................................................................................................. 1 1. INTRODUCTION .............................................................................................. 1 1.1. A history of aspirin ...................................................................................... 1 1.2. Properties and functions of aspirin ................................................................. 4 1.3. Metabolism of aspirin .................................................................................. 6 1.4. Platelets ...................................................................................................... 9 1.5. Aspirin resistance ...................................................................................... 16 1.6. Aspirin esterase ......................................................................................... 21 CHAPTER II ............................................................................................................... 24 2. MATERIALS and METHODS .......................................................................... 24 CHAPTER III ............................................................................................................. 40 3. CHARACTERIZATION AND IDENTIFICATION OF HUMAN PLASMA ASPIRIN HYDROLASES ........................................................................................ 40 3.1. Introduction .............................................................................................. 40 3.2. Results ...................................................................................................... 45 3.3. Discussion ................................................................................................ 72 CHAPTER IV ............................................................................................................. 78 4. IDENTIFICATION AND CHARACTORIZATION OF ASPIRIN HYDROLASE IN HUMAN ERYTHROCYTES .................................................................................... 78 4.1. Introduction .............................................................................................. 78 4.2. Results ...................................................................................................... 81 4.3. Discussion .............................................................................................. 104 CHAPTER V ............................................................................................................ 110 5. ELUCIDATION OF THE RELATIONSHIP BETWEEN ASPIRIN HYDROLASES AND ASPIRIN EFFICACY .................................................................................... 110 5.1. Introduction ............................................................................................ 110 viii 5.2. Results .................................................................................................... 112 5.3. Discussion .............................................................................................. 122 CHAPTER VI ........................................................................................................... 125 6. CONCLUSIONS AND DISCUSSIONS ............................................................... 125 7. BIBLIOGRAPHY .............................................................................................. 132 ix LIST OF FIGURES Figure 1 ........................................................................................................................................
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