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U Ottawa L.'Univcrsilc Cnnndicnnc Cnnadn's University Inn FACULTE DES ETUDES SUPERIEURES FACULTY of GRADUATE and ET POSTOCTORALES U Ottawa POSDOCTORAL STUDIES

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U Ottawa L.'Univcrsilc Cnnndicnnc Cnnadn's University Inn FACULTE DES ETUDES SUPERIEURES FACULTY of GRADUATE and ET POSTOCTORALES U Ottawa POSDOCTORAL STUDIES u Ottawa l.'Univcrsilc cnnndicnnc Cnnadn's university inn FACULTE DES ETUDES SUPERIEURES FACULTY OF GRADUATE AND ET POSTOCTORALES U Ottawa POSDOCTORAL STUDIES L'Universit(5 canadionne Canada's university Avtar LAL AUTEUR DE LA THESE / AUTHOR OF THESIS Ph.D. (Cellular and Molecular Medicine) GRADE/DEGREE Department of Cellular and Molecular Medicine 7AMTOC0L17D1PWE¥E^^ Role of Aldosterone in Cardiac Remodeling Post-Myocardial Infarction and After High Salt Diet TITRE DE LA THESE /TITLE OF THESIS Frans Leenen WEWEW(b7Rl~cfmc^^ CO-DIRECTEUR (CO-DIRECTRICE) DE LA THESE / THESIS CO-SUPERVISOR EXAMINATEURS (EXAMINATRICES) DE LA THESE / THESIS EXAMINERS Adolfo de Bold James Van Huysse Gordon Moe Stewart Whitman Gary W. Slater Le Doyen de la Faculte des etudes superieures et postdoctorales / Dean of the Faculty of Graduate and Postdoctoral Studies ROLE OF ALDOSTERONE IN CARDIAC REMODELING POST- MYOCARDIAL INFARCTION AND AFTER HIGH SALT DIET By Avtar Lai This Thesis is Submitted as a Partial Fulfillment of the Doctor of Philosophy Program in Cellular and Molecular Medicine, School of Graduate Studies Department of Cellular and Molecular Medicine Faculty of Medicine University of Ottawa © Avtar Lai, Ottawa, Canada, 2008 Library and Bibliotheque et 1*1 Archives Canada Archives Canada Published Heritage Direction du Branch Patrimoine de I'edition 395 Wellington Street 395, rue Wellington Ottawa ON K1A0N4 Ottawa ON K1A0N4 Canada Canada Your file Votre reference ISBN: 978-0-494-46514-1 Our file Notre reference ISBN: 978-0-494-46514-1 NOTICE: AVIS: The author has granted a non­ L'auteur a accorde une licence non exclusive exclusive license allowing Library permettant a la Bibliotheque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par telecommunication ou par Plntemet, prefer, telecommunication or on the Internet, distribuer et vendre des theses partout dans loan, distribute and sell theses le monde, a des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, electronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriete du droit d'auteur ownership and moral rights in et des droits moraux qui protege cette these. this thesis. Neither the thesis Ni la these ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent etre imprimes ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. In compliance with the Canadian Conformement a la loi canadienne Privacy Act some supporting sur la protection de la vie privee, forms may have been removed quelques formulaires secondaires from this thesis. ont ete enleves de cette these. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. Canada For my wife Jyoti and Children, Alisha and Karan 11 AUTHORIZATION Chapter 1: Figure 1: Reprinted from Journal of Endocrinology 2005; 186: 1-20. Connell M.C. and E. Davies. 2005. The new biology of aldosterone, with permission from Society for Endocrinology. Chapter 2: Reprinted from American Journal of Hypertension 2003; 16: 319-323. Lai, A., J.P. Veinot, and F.H.H. Leenen. Prevention of high salt diet-induced cardiac hypertrophy and fibrosis by spironolactone, with permission from Elsevier Limited. Chapter 3: Reprinted from Cardiovascular Research 2004; 64: 437-447. Lai, A., J.P. Veinot, and F.H.H. Leenen. Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats, with permission from Elsevier Health Science. Chapter 4: Reprinted from Journal of Molecular and Cellular Cardiology 2005; 39: 521- 529. Lai, A., J.P. Veinot, and F.H.H. Leenen. Prevention of cardiac remodeling after myocardial infarction in transgenic rats deficient in brain angiotensinogen, with permission from Elsevier Limited. in CONTRIBUTION OF COLLABORATORS All studies were conducted under the supervision of Frans H.H. Leenen at the University of Ottawa Heart Institute. All experimental work presented in Chapter 2 was carried out by Avtar Lai. All experimental work presented in Chapter 3 was carried out by Avtar Lai with the exception of coronary artery ligation, implantation of miniosmotic pump, and measurements of LV dP/dt max and plasma catecholamines. All experimental work presented in Chapter 4 was carried out by Avtar Lai with the exception of coronary artery ligation. The manuscripts presented in these chapters 2, 3, and 4 were written by Avtar Lai. Studies involving coronary artery ligation were performed by Hao Wang and Xiaohong Hou; studies involving implantation of miniosmotic pump and measurements of LV dP/dt max were performed by Bing Huang; and studies involving measurement of plasma catecholamines were carried out by Roselyn White. Scanning electron microscopy (SEM) was performed with the help of Ann-Fook Yang at the SEM lab, Agriculture Canada, Ottawa. IV ABSTRACT High Salt Diet Induces Cardiac Fibrosis by Activating Cardiac Aldosterone We hypothesized that enhanced cardiac aldosterone production by high salt intake may increase left ventricle (LV) weight and cardiomyocyte size and induce fibrosis in both ventricles. Regular salt (0.6%) or high salt (8%) diet, either without or with spironolactone (20 or 80 mg/kg/day) were given to Wistar rats for 4 and 8 weeks. Both LV weight and cardiomyocyte cross-sectional diameter were increased significantly by high salt diet after 4 and 8 weeks. Both LV and right ventricle (RV) collagen and fibrosis as well as mean arterial pressure (MAP) remained unchanged after 4 weeks, but increased significantly after 8 weeks on high salt diet. Spironolactone (80 mg/kg) prevented the high salt-induced increases in LV weight and cardiomyocyte cross-sectional diameter as well as LV and RV collagen and fibrosis, and attenuated the increase in MAP. Spironolactone (20 mg/kg) was somewhat less effective. The high salt induced changes in cardiac and cardiomyocyte hypertrophy, and cardiac fibrosis were prevented by spironolactone, which is consistent with the concept that cardiac aldosterone mediates these cardiac effects of high salt diet. Role of brain renin-angiotensin-aldosterone-system (RAAS) in cardiac remodeling post-MI To assess the contribution of the brain RAAS in the activation of the cardiac RAAS and remodeling post-MI, Wistar rats with intracerebroventricular (icv) infusion of spironolactone and transgenic (TG) rats deficient in brain angiotensinogen were studied. An MI was induced by acute coronary artery ligation. Spironolactone was administered v by icv infusion (100 ng/h) or orally (80 mg/kg/day) for 6 weeks post-MI in Wistar rats. TG rats and control Sprague-Dawley (SD) rats were followed for 8 weeks. MI decreased LV peak systolic pressure (LVPSP) and LV dP/dt max and increased LV end diastolic pressure (LVEDP) and plasma catecholamines and serum aldosterone, which were prevented or attenuated by both icv and oral spironolactone at 6 weeks post-MI. MI increased internal circumferences, cardiomyocyte diameter, fibrosis, laminin and fibronectin, and aldosterone in the LV or and RV, which were also significantly prevented/ inhibited by both icv and oral spironolactone at 6 weeks post-MI in Wistar rats as well as at 8 weeks post-MI in TG rats. Magnitude of beneficial effects of icv spironolactone at low doses was largely equal to that achieved with its oral administration at much higher doses, indicating that in addition to other sites of actions, aldosterone appears to activate central nervous system (CNS) pathways and thereby influences peripheral mechanisms involved in cardiac remodeling. The findings in TG rats support the pivotal role of locally produced angiotensin II in the brain in cardiac remodeling post- MI. The brain RAAS appears to activate a cascade of events, among others an increase in cardiac aldosterone, which play a major role in cardiac remodeling post-MI. VI TABLE OF CONTENTS Dedication --------- n Authorization --------- iii Contribution of Collaborators- ------ iv Abstract --------- v Table of Contents - vii List of Tables xi List of Figures- -------- xii List of Abbreviations -------- xvi Acknowledgements -------- xx Chapter 1--------- 1 General Introduction ------- 1 Preface --------- 2 1 Literature Review ------- 4 1.1 Production of Aldosterone in Different Tissues - - - 4 1.1.1 Aldosterone Synthesis in the Adrenal - - - - 4 1.1.1 -a Regulation of Synthesis of Aldosterone in Adrenal - - 7 1.1.1 -a-i Renin-Angiotensin System Regulating Adrenal Synthesis 8 1.1.1 -a-ii Potassium ions Regulating Adrenal Synthesis of Aldosterone 9 1.1.1 -a-iii ACTH Regulating Adrenal Synthesis of Aldosterone - 10 1.1.2 Aldosterone Synthesis in Brain - - - - - 10 1.1.2-a Regulation of Brain Synthesis of Aldosterone - - 14 1.1.2-a-i CSF [Na+] Regulating Brain Synthesis of Aldosterone - 14 1.1.2-a-ii Ang II Regulating Brain Synthesis of Aldosterone - 15 1.1.3 Cardiac Synthesis of Aldosterone - - - - 15 1.1.3-a Regulation of Cardiac Synthesis of Aldosterone - - 17 1.1.3-a-i Ang II Regulating Cardiac Synthesis of Aldosterone - 17 1.1.3-a-ii ACTH Regulating Cardiac Synthesis of Aldosterone - 18 1.1.3-a-iii Low Na+/high K+ diet Regulating Cardiac Synthesis
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