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Regulation of Cardiac Fibroblast Funtion Via Cyclic Amp, Collagen I, Iii, and Vi: Implications for Post-Myocardial Infarction Remodeling

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Regulation of Cardiac Fibroblast Funtion Via Cyclic Amp, Collagen I, Iii, and Vi: Implications for Post-Myocardial Infarction Remodeling REGULATION OF CARDIAC FIBROBLAST FUNTION VIA CYCLIC AMP, COLLAGEN I, III, AND VI: IMPLICATIONS FOR POST-MYOCARDIAL INFARCTION REMODELING A dissertation submitted to Kent State University in cooperation with the Northeastern Ohio Universities College of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy By Jennifer Elaine Naugle May, 2006 ii TABLE OF CONTENTS List of Figures……………………………………………………………… iii Acknowledgements………………………………………………………… v Abstract…………………………………………………………...…………vi List of abbreviations……………………………………………….............. viii Chapters I. Introduction Role of cardiac fibroblasts in the heart………………………… 1 G-protein coupled receptor signaling………………………….. 2 Role of myofibroblasts in the heart……………………………. 12 Collagen composition of the myocardial ECM…………………16 Collagen receptors and cardiac fibroblasts…………………….. 19 Receptors associated with type VI collagen and myofibroblast differentiation………………………………. 22 Myocardial infarction and pathological remodeling…………… 23 Specific aims and hypotheses………………………………….. 29 II. Mechanism of angiontensin II-induced cAMP production and functional consequences Introduction…………………………………………………….. 31 Methods…………………………………………………........... 34 Results………………………………………………………….. 39 Discussion………………………………………………............ 65 III. Type VI collagen induces cardiac myofibroblast differentia- tion: implications for post-infarction remodeling Introduction…………………………………………………….. 74 Methods…………………………………………………………76 Results………………………………………………………….. 80 Discussion……………………………………………………… 92 IV. Temporal changes in type VI collagen, myofibroblast content, and integrin receptors in rats post-myocardial infarction Introduction…………………………………………….. ………103 Methods…………………………………………………………105 Results………………………………………………….. ………108 Discussion……………………………………………….………114 V. Overall Conclusions……………………………………………… 126 VI. Bibliography…………………………………………...………… 136 iii LIST OF FIGURES 1. Angiotensin II signaling in cardiac fibroblasts…………………………………….. 5 2. β-adrenergic signaling in cardiac fibroblasts……………………………………...... 8 3. Angiotensin II potentiates β-adrenergic signaling in cardiac fibroblasts…………... 11 4. Differentiation of fibroblasts into mature myofibroblasts………………………….. 14 5. Structural differences between fibrillar collagen and type VI collagen……………. 18 6. Integrin receptor structure and interaction with ECM proteins……………………. 21 7. The role of cardiac fibroblasts in the progression of cardiac fibrosis……………… 27 8. Gq-Gs cross-talk is dependent upon Gq and phospholipase C activation………….. 41 9. Ionomyocin-induced intracellular transients enhance cAMP production………….. 45 10. Angiotensin II and ionomycin enhance forskolin-stimulated cAMP production…. 48 11. Intracellular Ca2+ transients enhance cAMP production and are blocked by Ca2+ chelation…………………………………………………………………………….51 12. Cardiac fibroblasts express multiple AC isoforms with different subcellular distributions……………………………………………………………………... 54 13. Calmidazolium and overexpression of AC6 inhibit cross-talk………………….. 57 14. Elevation of cAMP inhibits differentiation to cardiac myofibroblasts………….. 60 15. Gq-Gs cross-talk impacts cardiac fibroblast collagen synthesis………………… 64 16. Collagen I production is inhibited by elevations in cAMP via forskolin……….. 67 17. Proposed Gq-Gs cross-talk mechanism…………………………………………. 73 18. Type VI collagen induces cardiac myofibroblast differentiation……………….. 82 19. Collagen substrates and ANG II treatment differentially affect cardiac fibroblast iv proliferation……………………………………………………………………… 85 20. Treatment with ANG II induces type VI collagen expression…………………... 88 21. Coronary ligation in rats induces a collagen-rich infarcted myocardium……….. 91 22. Type VI collagen is elevated following post-myocardial infarction remodeling…. 94 23. Enhanced myofibroblast content in the infarcted rat myocardium……………… 97 24. Effects of the ECM on CF activation and the progression of cardiac fibrosis….. 102 25. Type VI collagen is elevated 7 and 14 days post-myocardial infarction.……….. 110 26. Myofibroblast content is significantly increased by 7 days post-MI……………. 113 27. αv integrin receptor subunit levels do not change within two weeks post-MI….. 116 28. Collagen VI interacts with the α3 integrin receptor in focal adhesions………… 119 29. α3 integrin is elevated 3 days and 16 weeks post-MI………………………….... 122 30. Temporal changes in type VI collagen, myofibroblast content, and α3 integrin following MI……………………………………………..……………………... 125 31. Factors effecting CF activation during the progression of cardiac fibrosis……... 131 v ACKNOWLEDGEMENTS I would like to thank everyone who has helped me and supported me throughout this process, especially my family and friends, who have always been there for me no matter what. My parents, Robert and Nancy Naugle, have been a wonderful, guiding force in my life and have always believed in me. My graduate mentor, Gary Meszaros, has challenged me to become a well-rounded scientist, and the rest of my doctoral committee has aided me greatly in many areas. My colleague and friend Erik Olson has also been there for me as a fellow scientist and as my pseudo-big brother. My best friend and love of my life, Andrew Bryant, has made this so much easier by reminding me not to take for granted the important things in life. I also would like to thank God for all of the blessings he has bestowed upon me, and for surrounding me with such amazing people in my life. vi ABSTRACT Cardiac fibroblasts (CFs) are the major non-contractile cells present in the myocardium, and are primary regulators of synthesis and secretion of extracellular matrix (ECM) proteins. Both proliferation and differentiation of CFs can potentially result in excess ECM protein production and cardiac fibrosis, a condition characterized by a stiffening of the myocardium. This condition is common after myocardial infarction and develops during heart failure, resulting in compromised cardiac function. Hormonal input, as well as input from the surrounding ECM can affect CF proliferation and/or differentiation, and an increase in either one of these parameters will result in elevated ECM production. Consequently, limiting prolonged fibroblast activation and the subsequent detrimental ECM production after myocardial infarction or heart failure might help to preserve left ventricular function. The specific ECM composition in the myocardium likely imparts significant effects on CF function. However, to date little is known about the effect of the ECM on CF function or the signaling pathways utilized by ECM molecules. In the adult, the myocardium is primarily composed of types I and III collagen, in addition to lower levels of types IV, V, and VI collagen. Extensive remodeling of the ECM occurs following myocardial infarction, and the resulting ECM composition can influence cardiac fibroblast activation in addition to affecting cardiac performance. My goals are to determine the mechanism of Gq/Gs cross-talk and the functional consequences in CFs, to determine the functional effects of specific types of collagen on vii CF differentiation and proliferation, and to identify the collagen composition and myofibroblast content post-myocardial infarction. viii LIST OF ABBREVIATIONS AC; adenylyl cyclase ANG II; angiotensin II α-SMA; α-smooth muscle actin β-AR; β-adrenergic receptor BAPTA/AM; 1,2-bis(o-Aminophenoxy)ethane-N,N,N,N’-tetra acetic acid Tetra(acetoxymethyl) Ester Ca2+; calcium cAMP; cyclic adenosine monophosphate CAV; caveolae CF; cardiac fibroblast ECM; extracellular matrix FSK; forskolin IN; ionomycin IP3; inositol 1,4,5--trisphosphate ISO; isoproterenol MI; myocardial infarction PCR; polymerase chain reaction PKA; protein kinase A PKC; protein kinase C TG; thapsigargin TGF-β; transforming growth factor-β 1 CHAPTER ONE INTRODUCTION Role of cardiac fibroblasts in the heart: Cardiac fibroblasts (CFs) comprise approximately 20% of the myocardial mass and account for over half of the cell number in the heart. In the adult myocardium, CFs are interspersed with cardiac myocytes, and this network of cells is embedded in the extracellular matrix (ECM). CFs are responsible for synthesis and secretion of ECM proteins, as well as secretion of the enzymes responsible for ECM degradation, the matrix metalloproteinases (MMPs) (Camelliti et al., 2005). CFs can secrete cytokines and growth factors which can act in an autocrine or paracrine manner. These cells can be stimulated by a variety of growth factors, hormones, and cytokines. Activation of CFs involves proliferation and/or differentiation to myofibroblasts, both of which can lead to excess ECM production and eventually cardiac fibrosis. Cardiac fibrosis is characterized by overproduction of ECM components and stiffening of the myocardium, and is often a secondary condition that develops in response to myocardial infarction, hypertension, or heart failure. The excessive ECM present in cardiac fibrosis is detrimental to cardiac function by decreasing compliance and serving as an obstacle for the cardiac conduction system. Decreased compliance, or stiffening of the myocardium, causes the heart to work harder with each beat in order to pump the same amount of blood, and interruption of the 2 cardiac conduction system makes the heart prone to arrhythmias, both of which are acutely and chronically detrimental to the heart. G-protein coupled receptor signaling: G-protein coupled receptors (GPCRs) are plasma membrane receptors that span the lipid bilayer seven times and couple to various heterotrimeric G proteins
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