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The Role of Aldehyde Dehydrogenase 2 in Nitrate Tolerance

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The Role of Aldehyde Dehydrogenase 2 in Nitrate Tolerance THE ROLE OF ALDEHYDE DEHYDROGENASE 2 IN NITRATE TOLERANCE by Yohan Philip D’Souza A thesis submitted to the Department of Pharmacology & Toxicology In conformity with the requirements for the degree of Master of Science Queen’s University Kingston, Ontario, Canada (September 2008) Copyright ©Yohan Philip D’Souza, 2008 Abstract Yohan P. D’Souza: The Role of Aldehyde Dehydrogenase 2 in Nitrate Tolerance. M.Sc. Thesis, Queen’s University, Kingston, September 2008. Organic nitrates such as glyceryl trinitrate (GTN) are commonly used to treat myocardial ischemia and congestive heart failure. GTN is proposed to act as a prodrug that requires bioactivation for pharmacological activity. However, continuous administration results in tolerance development, limiting its clinical usefulness. Aldehyde dehydrogenase 2 (ALDH2) has been proposed to be the primary enzyme responsible for GTN bioactivation, and ALDH2 inactivation has been proposed as the sole basis of nitrate tolerance. In the present study, we utilized an in vivo GTN tolerance model to investigate the role of ALDH2 in GTN bioactivation and tolerance. We assessed changes in ALDH2 protein, mRNA and activity levels in rat blood vessels during chronic GTN exposure (0.4 mg/hr for 6, 12, 24 and 48 hr) in relation to changes in vasodilator responses to GTN. A time-dependent decrease in both ALDH2 expression and activity occurred (80% in tolerant veins and 30% in tolerant arteries after 48 hrs exposure to GTN), concomitant with decreased vasodilator responses to GTN. However, after a 24 hr drug-free period following 48 hr GTN exposure, the vasodilator responses to GTN had returned to control values, whereas ALDH2 expression and activity were still markedly depressed. The dissociation between reduced ALDH2 activity and expression, and the duration of the impaired vasodilator responses to GTN in nitrate-tolerant blood vessels, suggest factors other than changes in ALDH2-mediated GTN bioactivation contribute to nitrate tolerance. ii Co-Authorship This thesis was based on research conducted by Yohan D’Souza under the supervision of Dr. Brian Bennett. All data was obtained and analyzed by Yohan D’Souza with the exception of the qRT-PCR, which was completed by Dr. Yanbin Ji. iii Acknowledgements I would like to take this opportunity to thank the many people who have supported me over these past two years. I sincerely thank my supervisor Dr. Brian Bennett who has mentored me and guided me through this project. He has not only helped me grow academically but has taught me valuable life lessons. His support and guidance made this degree a pleasure. I thank him for the opportunity to undertake this project. I would also like to thank Dr. Yanbin Ji who provided his technical assistance whenever I needed it. He was always there to help clarify research or any other problem I had. A special thank you to Diane Anderson for her patience and technical assistance. She was always willing to help no matter what needed to be done. Finally a thank you to the Pharmacology & Toxicology department for this opportunity, the friends I have made and all the great times I have had along the way. iv Dedication To my family who offered me unconditional love and support throughout this thesis v Table of Contents ABSTRACT…………………………………………………….………..……………....ii STATEMENT OF CO-AUTHORSHIP……………………………...……….…...…..iii ACKNOWLEDGEMENTS……………………………………...………………….….iv DEDICATION…………………………………………………..…….…..………….….v TABLE OF CONTENTS……………………………………………...….………….....vi LIST OF FIGURES…………………………………………………...………...…......viii LIST OF TABLES……………………………………………………………………….x LIST OF ABBREVIATIONS………………………………….…...………...……..….xi CHAPTER 1: INTRODUCTION 1.1 Cardiovascular disease……………………………………………………....1 1.2 Statement of the Research Problem………………………………………...2 1.3 Pharmacology of Organic Nitrates………………………………………….5 1.3.1 Structure and Chemistry ………………………………...……….. 5 1.3.2 Clinical use of Organic Nitrates…………………………………...6 1.3.3 Pharmacological Effects of Organic Nitrates…………………….. 7 1.3.4 Mechanisms of Action………..………………………………….. 9 1.3.5 Tolerance to Organic Nitrates……………………………………10 1.4 Biotransformation of Organic Nitrates……………………………………12 1.4.1 Clearance-based and Mechanism-based Biotransformation……..12 1.4.2 Enzymatic Biotransformation of GTN………...………………... 13 1.5 Aldehyde Dehydrogenase 2……………………………………………….. 17 1.5.1 Implications in Nitrate Tolerance………………………..……… 17 1.5.2 Structure and Localization of ALDH2………………………….. 18 1.5.3 ALDH2*2……………………………………………………….. 19 1.5.4 Proposed Role for ALDH2 in GTN Bioactivation and Tolerance.21 1.5.5 Past Studies………………...…………………………………….25 1.6 Rationale, Research Hypothesis and Objectives……….…………………29 CHAPTER 2: MATERIALS AND METHODS 2.1 Drugs and Solutions…………………………………………….31 2.2 Animals…………………………………………………………. 31 2.3 Induction of GTN Tolerance in Vivo…………………………..32 2.4 Isolated Blood Vessel Relaxation Responses….……………… 33 2.4.1 Preparation……………………………………………….33 2.4.2 Relaxation Responses……..……………………………..34 2.5 Biochemical Analysis…………………………………………... 34 2.5.1 Protein Determination……………………………………34 2.5.2 Immunoblot analysis of ALDH2…………………….….. 35 2.5.3 ALDH Activity………………………………………...... 36 2.6 qRT-PCR……………………………………………………….. 36 2.7 Data Analysis…………………………………………………… 37 vi CHAPTER 3: RESULTS 3.1 ALDH2 Protein Expression……………………………………38 3.2 ALDH2 Activity………………………………………………...46 3.3 Relaxation Responses to GTN…………………………...…….39 3.3.1 Aorta……………………………………………………..39 3.3.2 Femoral Artery…………………………………………..46 3.3.3 Femoral Vein…………………………………………….49 3.4 PCR Analysis………………………………………………..….55 CHAPTER 4: DISCUSSION AND FUTURE DIRECTIONS……………..………..57 REFERENCES…………………………………………………………………………66 vii List of Figures Figure 1-1: Structure of GTN and some other organic nitrates Figure 1-2: The mechanism of action of GTN detailing the clearance-based and mechanism-based pathways Figure 1-3: Structure of ALDH2 tetramer Figure 1-4: Structure of ALDH2 monomer Figure 1-5: Proposed mechanism of bioactivation of GTN by ALDH2 Figure 3-1: Immunoblot analysis of vessel specific ALDH2 expression during chronic GTN-treatment and recovery Figure 3-2: Changes in ALDH2 protein levels expressed as a percentage of sham in aorta from GTN-treated animals. Figure 3-3: Changes in ALDH2 protein levels expressed as a percentage of sham in femoral arteries from GTN-treated animals. Figure 3-4: Changes in ALDH2 protein levels expressed as a percentage of sham in vena cava from GTN-treated animals. Figure 3-5: Changes in ALDH2 protein levels expressed as a percentage of sham in femoral veins from GTN-treated animals. Figure 3-6: Changes in total ALDH activity during chronic GTN-treatment and recovery in rat aorta. Figure 3-7: Effect of chronic GTN exposure on GTN-induced relaxation of isolated femoral arteries. Figure 3-8: Effect of GTN-free period following a 48 hour GTN exposure on GTN- induced relaxation of isolated femoral arteries. Figure 3-9: Effect of chronic GTN exposure on GTN-induced relaxation of isolated femoral veins. Figure 3-10: Effect of GTN-free period following a 48 hour GTN exposure on GTN- induced relaxation of isolated femoral veins. Figure 3-11: Effect of chronic GTN- exposure on ALDH2 mRNA expression. viii Figure 4-1 Proposed mechanism of GTN tolerance ix List of Tables Table 3-1: EC50 values for GTN induced relaxation responses in femoral artery and vein. x List of Abbreviations 1,2-GDN glyceryl-1,2-dinitrate 1,3-GDN glyceryl-1,3-dinitrate 4-HNE 4-hydroxynonenal ALDH2 aldehyde dehydrogenase 2 ALDH2*1 Heterozygous for Glu504Lys mutation ALDH2*2 Homozygous Glu504Lys mutation cGMP 3’,5’-cyclic guanosine monophosphate CYP450 cytochrome P450 Cys cysteine DEA/NO Diethylamine-nonoate DTT dithiothreitol eNOS endothelial nitric oxide synthase ETC electron transport chain Gqα Gα subunit of the Gq class of G proteins GTN glyceryl trinitrate GST glutathione transferase IL interleukin IP3 inositol-1,4,5-triphosphate IRAG inositol 1,4,5-trisphophate receptor-associated cGMP kinase substrate ISDN isosorbide dinitrate ISMN isosorbide mononitrate MLCP myosin light chain phosphatase NADPH nicotinamide adenine dinucleotide phosphate NO Nitric oxide - NO 2 Inorganic nitrite anion PKG cGMP-dependent protein kinase qRT-PCR Quantitative real-time Polymerase chain reaction RhoA Ras homolog gene family, member A RGS2 Regulator of G-protein signaling 2 ROS reactive oxygen species sGC soluble guanylyl cyclase SH sulfhydryl SNO S-nitrosothiol SNP sodium nitroprusside VSM vascular smooth muscle XO xanthine oxidase xi Chapter 1 Introduction 1.1 Cardiovascular Disease Organic nitrates, such as glyceryl trinitrate (nitroglycerin, GTN), have been used in clinical practice for more than a century. Cardiovascular disease accounts for over 16.7 million deaths worldwide (one third of all deaths). In Canada, 41% of the economic burden of illness is attributed to cardiovascular disease (Canadian Institute for Health Information 2000). Ischemic heart disease is a primary contributor to the prevalence of cardiovascular disease, and angina pectoris is a principle symptom of ischemia (Katzung & Parmley, 1998). In Canada, angina pectoris affects 1 in 50 people. The primary cause of angina pectoris is an imbalance between myocardial oxygen supply and demand, and it is frequently caused by atherosclerotic coronary artery disease. Furthermore, in 2001, GTN was prescribed to treat angina more than 2 million times in the United States alone (Zaher et al., 2004). Thus, a reduction in the number of cases and optimized treatment of cardiovascular diseases could decrease the mortality
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