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ROLE of ARGINASE 2 by Esraa Farid Aly Shosha October

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ROLE of ARGINASE 2 by Esraa Farid Aly Shosha October NEUROVASCULAR DEGENERATION FOLLOWING RETINAL ISCHEMIA REPERFUSION INJURY: ROLE OF ARGINASE 2 By Esraa Farid Aly Shosha Submitted to the Faculty of the Graduate School of Augusta University in partial fulfillment of the Requirements of the Degree of (Doctor of Philosophy) October 2017 COPYRIGHT© 2017 by Esraa Shosha ACKNOWLEDGEMENTS I would like to thank my mentor, Dr. Ruth Caldwell, for giving me the opportunity to join her lab and pursue my studies under her guidance. It was a great pleasure to work under her mentorship. Dr. Caldwell not only teaches you how to do research, but sets a role model of a great scientist and human being. I am blessed to be mentored by her. I would like to extend my gratitude to the current lab members: Ms. Tahira Lemtalsi, Dr. Abdelrahman Fouda, Ms. Zhimin Xu, Dr. Modesto Rojas and a previous lab member, Dr. Chintan Patel. I also would like to thank Dr. Priya Narayanan for her continuous guidance and help during my period of studies. Dr. Narayanan and Ms. Lemtalsi, thank you for being my family in Augusta. I would like to acknowledge my committee members for their time and scientific contribution: Dr. David Fulton, Dr. William Caldwell, Dr. Mohamed Al-Shabrawey and Dr. Priya Narayanan. I also would like to thank the thesis reader, Dr. Anilkumar Pillai. This work wouldn’t have been accomplished without the help of our collaborators: Dr. William Caldwell’s lab, Dr. Mohamed Al-Shabrawey’s lab and Dr. David Fulton’s lab. I also would like to thank the vascular biology center (VBC) graduate program for providing an intense training environment. I specially thank Dr. Rudolf Lucas for his great support and help. Thanks to the staff of the graduate school for the great help. I dedicate this thesis to my mother (Mrs. Mervat Ahmed) and my father (Dr. Farid Shosha) for having faith in me, raising me the way I am and encouraging me in times of difficulties throughout my life. I also would like to extend my sincere gratitude to my brother (Dr. Mohamed Shosha) and my sister (Dr. Alaa Shosha) for your invaluable support and humor. Special thanks and dedication go to my small family for their sacrifice along the way to make this dream come true. To my dear husband (Dr. Abdelrahman Fouda), for your love, patience, friendship and support. To my precious daughters (Alia and Farida), you are the inspiration for me to keep going on. ABSTRACT ESRAA SHOSHA Neurovascular Degeneration Following Retinal Ischemia Reperfusion Injury: Role of Arginase 2 (Under the direction of RUTH B. CALDWELL) Ischemic retinopathies such as retinopathy of prematurity, central retinal artery occlusion and diabetic retinopathy are leading causes of visual impairment and blindness. These pathologies share common features of oxidative stress, activation of inflammatory pathways and neurovascular damage. There is no clinically effective treatment for these conditions because the underlying mechanisms are still not fully understood. In the current study, we used a mouse model of retinal ischemia reperfusion (I/R) insult to explore the underlying mechanisms of neurovascular degeneration in ischemic retinopathies. The arginase enzyme utilizes the L-arginine amino acid for the production of L-ornithine and urea. Here, we investigated the role of the mitochondrial arginase isoform, arginase 2 (A2) in retinal I/R induced neurovascular injury. We found that retinal I/R induced neurovascular degeneration, superoxide and nitrotyrosine formation, glial activation, cell death by necroptosis and impairment of inner retinal function in wild type (WT) mice. A2 homozygous deletion (A2-/-) significantly protected against the neurovascular degeneration after retinal I/R. That was attributed to decreased oxidative stress and glial activation. A2 deletion protected against I/R induced retinal function impairment. Using Optical coherence tomography (OCT), we evaluated the retinal structure in live animals and found that A2-/- retinas showed a more preserved structure and less retinal detachment. To investigate the underlying mechanisms of A2 induced vascular damage after I/R, we used an in vitro model of oxygen glucose deprivation/ reperfusion (OGD/R) in bovine retinal endothelial cells (BRECs). Analysis of oxidative metabolism showed impaired mitochondrial function. We also found an increase in dynamin elated protein 1 (Drp1), a mitochondrial fission marker. Mitochondria labeling studies showed fragmented mitochondria after OGD/R. Arginase inhibition reduced mitochondrial fragmentation in OGD/R insult. This dissertation presents A2 as a new therapeutic target in reducing neurovascular damage in ischemic retinopathies. KEY WORDS: retinal ischemia, arginase, neurovascular degeneration, mitochondria Table of Contents Chapter Page 1 Chapter I: Introduction .......................................................................................3 A) Statement of the problem and specific aims of the overall project ..........3 B) Literature review ......................................................................................6 C) Rationale .................................................................................................25 2 Chapter II: Arginase 2 Promotes Neurovascular Degeneration During Ischemia/Reperfusion Injury (published manuscript) ....................................................... 27 3 Chapter III: Mechanisms of Retinal Ischemia/Reperfusion Injury: Arginase 2 and the Mitochondria (unpublished data) ..........................................................................62 4 Chapter IV: Discussion ....................................................................................85 5 Chapter V: Summary .......................................................................................93 References ..........................................................................................................................96 List of Tables Table 1: List of abbreviations used in the text .....................................................................1 Table 2: Time points of mice sacrifice after I/R and rationale for each ............................54 List of Figures Figure 1: Summary of the proposed study ...........................................................................5 Figure 2: Scheme for L-arginine catabolism .......................................................................6 Figure 3: Scheme for polyamines production ......................................................................7 Figure 4: Oxygen induced retinopathy (OIR) mouse model ............................................14 Figure 5: Schematic diagram for retinal structure .............................................................17 Figure 6: Retinal blood supply ...........................................................................................18 Figure 7: Retinal ischemia reperfusion (I/R) mouse model ...............................................21 Figure 8: Increased expression of arginase 2 following I/R injury ....................................33 Figure 9: A2 deletion prevented I/R injury-induced retinal thinning ................................35 Figure 10: A2 deletion reduced I/R injury-induced necroptic cell death ...........................37 Figure 11: A2 deletion prevented I/R injury-induced loss of ganglion cell layer neurons ......................................................................................................................38 Figure 12: A2 deletion prevented I/R injury-induced microvascular degeneration ..........40 Figure 13: A2 deletion limited I/R injury-induced glial activation ...................................41 Figure 14: A2 deletion prevented I/R injury-induced oxidative stress ..............................44 Figure 15: A2 deletion prevented I/R injury-induced impairment of inner retina function ....................................................................................................................46 Figure 16: Possible mechanisms of neurovascular degeneration after retinal I/R ............48 Figure 17: A2 deletion reduces I/R injury-induced increases in Drp1 ..............................68 Figure 18: A2 expression and cell stress response increase in endothelial cells after OGD/R ...............................................................................................................................69 Figure 19: Arginase inhibition protects against OGD/R induced mitochondrial fission ...71 Figure 20: OGD/R induces mitochondrial dysfunction .....................................................73 Figure 21: A2 deletion preserves retinal structure and prevents retinal detachment .........75 Figure 22: Summary of the role of A2 in inducing neurovascular degeneration following retinal I/R injury .................................................................................................................95 Table 1 Abbreviation Term A1 Arginase 1 A2 Arginase 2 A2-/- A2 Homozygous Knockout ABH 2-(S)-Amino-6-Boronohexanoic Acid AD Alzheimer’s Disease ADMA Asymmetric Dimethylarginine APAO N(1)-acetylpolyamine oxidase BDNF Brain-Derived Neurotrophic Factor BH4 Tetrahydrobiopterin BRECs Bovine Retinal Endothelial Cells BSA Bovine Serum Albumin CNS Central Nervous System CRAO Central Retinal Artery Occlusion DR Diabetic Retinopathy Drp1 Dynamin Related Protein 1 eNOS or NOS III Endothelial Nitric Oxide Synthase ERK Extracellular Signal-Regulated Kinase FBS Fetal Bovine Serum GCL Ganglion Cell Layer INL Inner Nuclear Layer iNOS or NOS II Inducible Nitric Oxide Synthase IOP
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