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UNIVERSITY OF CINCINNATI Date: ___ Feb 20th, 2008 I, Siyun Liao, hereby submit this work as part of the requirements for the degree of: ________________Doctor of Philosophy in: Molecular, Cellular and Biochemical Pharmacology It is entitled: ____The Role of Fibroblast Grown Factor-2 Isoforms in ___Ischemia-Reperfusion Injury and Cardioprotection This work and its defense approved by: Chair: Jo El J. Schultz, Ph.D. Thomas Doetschman, Ph.D. W. Keith Jones, Ph.D. Evangelia G. Kranias, Ph.D. Mark Olah, Ph.D. Hong-Sheng Wang, Ph.D. THE ROLE OF FIBROBLAST GROWTH FACTOR-2 ISOFORMS IN ISCHEMIA- REPERFUSION INJURY AND CARDIOPROTECTION A dissertation submitted to the Division of Graduate Studies of the University of Cincinnati In partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY In the Department of Pharmacology and Cell Biophysics 2007 by Siyun Liao B.S. China Pharmaceutical University, 2000 Committee Chair: Dr. Jo El J. Schultz ii Abstract Cardiovascular disease (CVD) remains the leading cause of death in the United States and in the developing world, with ischemic heart disease the second most common form of CVD. Experimental and clinical studies have demonstrated that a number of interventions, including brief periods of ischemia or hypoxia and certain endogenous molecules such as growth factors, opioids, adenosine or pharmacological agents are capable of protecting the heart against post- ischemic cardiac dysfunction, arrhythmias and myocardial infarction. One of these growth factors, fibroblast growth factor-2 (FGF2), has been implicated to be a cardioprotective molecule. FGF2 consists of multiple protein isoforms (low molecular weight, LMW, and high molecular weight, HMW) produced by alternative translation from the Fgf2 gene and these protein isoforms are localized to different cellular compartments indicating unique biological activity. Currently, the roles of the FGF2 isoforms in ischemia-reperfusion injury and cardioprotection remain to be elucidated. Understanding the biological function(s) of the FGF2 isoforms in cardioprotection is of a great clinical importance and may lead to the development of novel pharmacological or gene therapy strategies for ischemic heart disease. This dissertation research utilized mice with a targeted ablation of a specific FGF2 isoform (FGF2 LMWKO or FGF2 HMWKO) or mice in which all FGF2 isoforms (Fgf2 KO) were absent, and mice with a ubiquitous overexpression of the human FGF2 HMW 24 kD isoform (24 kD Tg) to evaluate the role(s) of the FGF2 protein isoforms in ischemia-reperfusion (I/R) injury. Cardioprotection in mice subjected to an isolated work-performing heart model of global, low-flow ischemia-reperfusion injury was indicated as an improvement in post-ischemic recovery of cardiac function and/or a reduction in creatine kinase release into coronary effluent or a reduction in myocardial infarct size. FGF2 LMWKO hearts had a significant decrease in iii post-ischemic cardiac function compared to wildtype hearts (p<0.05). FGF2 HMWKO hearts, however, had a significantly enhanced post-ischemic recovery of cardiac function (p<0.05). Furthermore, in human FGF2 HMW 24 kD Tg hearts, the post-ischemic recovery of cardiac function was significantly decreased compared to non-transgenic hearts (p<0.05). Myocardial cell injury was not different between either Wt, Fgf2 KO, FGF2 HMWKO and FGF2 LMWKO or 24 kD Tg and NTg hearts after I/R injury indicating that all the isoforms were necessary to protect the heart from myocardial cell injury. The effect of FGF2 isoforms on I/R injury was independent of changes in coronary flow or blood vessel density. The cardioprotective effect mediated by the FGF2 LMW isoform was abolished when the mixed lineage kinase (MLK)/mitogen kinase kinase (MKK)/c-Jun N-terminal kinase (JNK) signaling pathway or FGF receptor (FGFR) was inhibited. The LMW isoform significantly inhibited MKK7, JNK, and c- Jun activation as well as apoptotic processes prior to and during ischemia–reperfusion injury (p<0.05). The cardioprotective effect of FGF2 LMW isoform occurred through modulating apoptosis via inhibition of c-Jun and JNK activation. The cardioprotective effect of the LMW isoform also required the involvement of FGF receptor (FGFR), most likely the murine FGFR1. Another potential mechanism involved in the LMW isoform-mediated cardioprotection may be due to its actions on cardiac gene expression as preliminary results indicated that the LMW isoform decreased cardiotoxic gene expression and increased cardioprotective gene expression. The FGF2 HMW isoforms significantly decreased the activation of PKC α and increased the activation of PI3-kinase and NFκB signaling pathways that are involved in cardioprotection (p<0.05). In addition, the FGF2 HMW isoforms regulated expression of genes involved in ischemia-reperfusion injury, gene transcription, and apoptosis. These genes could be potential targets regulated by FGF2 HMW isoforms during I/R injury. Together, these data show that the iv FGF2 LMW isoform had a beneficial role in protecting the heart from myocardial dysfunction while FGF2 HMW isoforms had a deleterious role in I/R injury. This dissertation provided a novel signaling mechanism of the LMW FGF2 isoform which could contribute to the cardioprotective effect. Though the mechanisms of the FGF2 HMW isoforms remain to be thoroughly characterized, this dissertation provides critical evidence for the role of the FGF2 HMW isoforms in ischemia-reperfusion injury including up-regulation of cardiotoxic gene expression and modulating transcription factor NF-κB. Together, these data show that the FGF2 LMW isoform has a beneficial effect, while FGF2 HMW isoforms have a detrimental effect in ischemia-reperfusion injury and the modulation of signals including FGFR, MAPK, NF-κB, c- JUN, and calcium leads to the differential outcomes on post-ischemic recovery of cardiac function and myocardial infarction. v Acknowledgments There are many people to whom I am deeply grateful and it may not be possible to individually acknowledge here. But, even within that large list, it would be impossible not to mention those who have made an immense imprint. I am indebted to my advisor, Dr. Jo El Schultz, who made this dissertation possible. I thank her for the personal and scientific growth I’ve experienced in my years as a graduate student as well as for the training, support, advice and patience I’ve received. I consider her not only a professional role model but a valued friend. I would like to thank my committee members, Dr. Thomas Doetschman, Dr. Keith Jones, Dr. Evangelia Kranias, Dr. Mark Olah and Dr. Hong-sheng Wang, for the valuable time, comments and assistance that each has provided toward my graduate training and dissertation research. Their guidance, scientific suggestions and careful review of my work aided and enhanced my graduate research experience and this dissertation significantly. I would also like to display my appreciation to the many past and present members of the Schultz lab. Special thanks to Gilbert Newman who devotes countless time and his expertise on the working-heart model of ischemia-reperfusion injury. I would also like to thank my past and present lab mates, Dr. Stacey House, Craig Bolte, Darius Porter, Nicolae Vatamaniuc, Janet Bodmer and Dan Pietras who have contributed greatly, their time, assistance, ideas, guidance and amazing friendship throughout my graduate training. I am also grateful to my collaborators, without whom I could not have accomplished the work presented here. Dr. Xiaoping Ren constantly helped section the hearts and take picture for vi measurement of infarct size even when he was also fighting for his own time. Special thanks to Sharon Pawlowski, Maureen Bender and Angel Whitaker for their excellent animal husbandry work which has supported this project. Also, a very special thanks to Dr. Ming Zhao and Dr. Azhar Mohamad, who both have been working on the creation of my mouse models for over ten years. Without these mouse models in place in the laboratory, my research project would not be significantly developed. Over the six years of my graduate study in the Department of Pharmacology and Cell Bbiophysics, I made friends with many students and staff. I especially want to thank Michael Tabet and Ming Dong for their support and assistance. Also, the members of the Department have provided me great assistance and moral support as well. Finally, I would also like to thank all the friends I made in Cincinnati, especially my boyfriend, Zhimin Peng, for his constant emotional support. 最重要的一点，我想把这本论文献给我的爸爸妈妈。 在我的人生中，是他们在最困难的 时候支持我，鼓励我，在我取得的成果的时候祝福我，无条件的爱我。 他们为我提供了 物质上，生活上，精神上的支持和鼓励。 没有他们，我就无法完成我的博士研究。 vii TABLE OF CONTENTS Page Abstract iii Acknowledgments vi Introduction 1 1. Ischemia-reperfusion injury 1 A. Ischemic injury 2 B. Reperfusion injury 3 C. Protecting the heart from ischemia-reperfusion injury 5 2. Fibroblast growth factor-2 6 A. Fibroblast growth factor family 6 B. Fibroblast growth factor-2 9 Fgf2 gene 9 FGF2 protein isoforms 10 FGF2 expression pattern 11 FGF2 isoform subcellular localization and release 12 C. FGF receptor 16 Heparan sulfate proteoglycans (HSPGs) 16 Fibroblast growth factor receptors (FGFRs) 17 Fibroblast growth factor receptor signaling 18 D. Biological activity of FGF2 isoforms 21 Blood vessels 21 Blood cells 22 Lung 23 viii Nervous system 24 Heart 25 E. FGF2 isoforms and transcription factors 26 F. Characteristics of mice deficient and overexpressing the Fgf2 gene 29 G. FGF2 isoforms and ischemia-reperfusion injury 30 H. FGF2 and calcium homeostasis 33 3. Protein kinases and cardiac ischemia-reperfusion injury 34 A. Protein kinase C 34 B. Mitogen activated protein kinases (MAPK) 39 Mixed lineage kinase (MLK) 39 c-Jun terminal kinase (JNK) 40 p38 MAPK 44 Extracellular signal-regulated kinase (ERK1/2) 46 C. PI-3 kinase and Akt 50 4. Cell death and ischemia-reperfusion injury (I/R) 52 A. Apoptosis 52 B. Oncosis 53 C. Cell death in cardiac ischemia-reperfusion injury 54 D. FGF2 and apoptotic cell death 55 5.
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