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MECHANISM of 12/15 LIPOXYGENASE-INDUCED RETINAL MICROVASCULAR DYSFUNCTION in DIABETIC RETINOPATHY by Khaled El Masry May 2018 CO

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MECHANISM of 12/15 LIPOXYGENASE-INDUCED RETINAL MICROVASCULAR DYSFUNCTION in DIABETIC RETINOPATHY by Khaled El Masry May 2018 CO MECHANISM OF 12/15 LIPOXYGENASE-INDUCED RETINAL MICROVASCULAR DYSFUNCTION IN DIABETIC RETINOPATHY By Khaled El Masry Submitted to the Faculty of the Graduate School of Augusta University in partial fulfillment of the Requirements of the Degree of (Doctor of Philosophy) May 2018 COPYRIGHT© 2018 by Khaled El Masry ACKNOWLEDGEMENTS I would like to thank my mentor Dr. Mohamed Al-Shabrawey for his help during my Ph.D. studies. I would like to thank all current and previous lab members, particularly Dr. Ahmed Ibrahim and Dr. Khaled Hussein for their continuous help and support since I joined the lab. I would like to acknowledge my committee members; Dr. Ruth Caldwell, Dr. David Fulton, Dr. Manuela Bartoli and Dr. Amany Tawfik for their great suggestions and guidance. I would like to thank my thesis reader Dr. Yutao Liu who is a great collaborator as well. I would like to thank the Graduate School for the continuous support for the students. Special thanks to Dr. Mitchell Watsky and Dr. Patricia Cameron, who offered me a non-stop help. I would like to thank the Cell Biology and Anatomy graduate program for the extended environment of knowledge that the graduate students enjoy during their training period. I specially thank Dr. Sylvia Smith and Dr. Mark Hamrick. I would like to thank everyone who taught me something one day since I was born. Thanks are due to all my teachers since kindergarten till my Ph.D. studies. Great appreciation is due to my family that tolerated me and supported me throughout all these years particularly my father (Dr. Mohammad Elmasry), my mother (Mrs. Hanem Hussein) and my brothers (Dr. Moaataz Elmasry and Dr. Ahmad Elmasry). Special thanks to my dear wife (Dr. Samar Habib) and my lovely kids (Anas, Albaraa and Aesha). I would dedicate this work and any success that I did or I will achieve to the soul of my father whom I lost one week before carrying my bags and travel to USA to start my Ph.D. My dad insisted that I have to travel to gain my Ph.D. while he was in the hospital after a major surgery and he felt that these days were his last ones. My dad was keen that I succeed and I hope I was able to make his wishes true. ABSTRACT KHALED EL MASRY Mechanism of 12/15 Lipoxygenase-Induced Retinal Microvascular Dysfunction in Diabetic Retinopathy (Under the direction of MOHAMED Al-SHABRAWEY) Our earlier studies have established the role of 12/15-lipoxygenase (LO) in mediating the inflammatory reaction in diabetic retinopathy. However, the exact mechanism is still unclear. The goal of the current study was to identify the potential role of endoplasmic reticulum (ER) stress as a major cellular stress response in the 12/15-LO- induced retinal changes in diabetic retinopathy. We used in vivo and in vitro approaches. For in vivo studies, experimental diabetes was induced in wild-type (WT) mice and 12/15-Lo (also known as Alox15) knockout mice (12/15-Lo−/−); ER stress was then evaluated after 12-14 weeks of diabetes. We also tested the effect of intravitreal injection of 12-hydroxyeicosatetraenoic acid (HETE) on retinal ER stress in WT mice and in mice lacking the catalytic subunit of NADPH oxidase, encoded by Nox2 (also known as Cybb) (Nox2−/− mice). In vitro studies were performed using human retinal endothelial cells (HRECs) treated with 15-HETE (0.1 µmol/l) or vehicle, with or without ER stress or NADPH oxidase inhibitors. This was followed by evaluation of ER stress response, NADPH oxidase expression/activity and the levels of phosphorylated vascular endothelial growth factor receptor-2 (p-VEGFR2) by western blotting and immunoprecipitation assays. Moreover, real-time imaging of intracellular calcium (Ca2+) release in HRECs treated with or without 15-HETE was performed using confocal microscopy. Deletion of 12/15-Lo significantly attenuated diabetes-induced ER stress in mouse retina. In vitro, 15-HETE upregulated ER stress markers such as phosphorylated RNA-dependent protein kinase-like ER-regulated kinase (p-PERK), activating transcription factor 6 (ATF6) and protein disulfide isomerase (PDI) in HRECs. Inhibition of ER stress reduced 15-HETE-induced-leukocyte adhesion, VEGFR2 phosphorylation and NADPH oxidase expression/activity. However, inhibition of NADPH oxidase or deletion of Nox2 had no effect on ER stress induced by the 12/15-LO-derived metabolites both in vitro and in vivo. We also found that 15-HETE increases the intracellular calcium in HRECs. ER stress contributes to 12/15-LO-induced retinal inflammation in diabetic retinopathy via activation of NADPH oxidase and VEGFR2. Perturbation of calcium homeostasis in the retina might also play a role in linking 12/15-LO to retinal ER stress and subsequent microvascular dysfunction in diabetic retinopathy. KEY WORDS: Bioactive lipids; Calcium; Diabetic retinopathy; Eicosanoids; ER stress; 12-HETE; 15-HETE; 12/15-Lipoxygenase; NADPH oxidase; VEGFR2 Table of Contents Chapter Page 1 Chapter I: INTRODUCTION ..........................................................................2 A) Statement of the problem and specific aims of the overall project.................................2 B) Literature review .............................................................................................................7 B.1. Retina: Development, Anatomy and Physiology...................................7 B.1.1. Eye and Retina Development .............................................................7 B.1.2. Macroanatomy of the Retina ............................................................10 B.1.3. Microanatomy of the Retina .............................................................12 B.1.4. Blood Supply of the Retina ...............................................................22 B.1.5. The Outer and Inner Blood Retinal Barriers .....................................24 B.1.6. Retinal Physiology ............................................................................25 B.2. Retinal Pathology .................................................................................27 B.2.1. Diabetic Retinopathy ........................................................................28 B.3. Bioactive Lipids ...................................................................................40 B.3.1. Eicosanoids .......................................................................................40 B.3.2. Bioactive Lipids and Retinopathies ..................................................48 B.3.3. 12/15-LO (ALOX15) ........................................................................51 B.4. ER Stress ..............................................................................................59 2 Chapter II: MATERIALS AND METHODS ................................................62 3 Chapter III: RESULTS....................................................................................70 4 Chapter IV: DISCUSSION .............................................................................85 5 Chapter V: SUMMARY..................................................................................91 REFERENCES .................................................................................................................93 List of Tables Table 1: Abbreviations list ...................................................................................................1 Table 2: Antibodies used in the experiments .....................................................................65 Table 3: Primers used in the experiments ..........................................................................67 List of Figures Figure 1: Conceptual frame of the central hypothesis of the proposed studies ...................6 Figure 2: Eye and retinal development ................................................................................8 Figure 3: Eye anatomy illustration .....................................................................................11 Figure 4: Retinal cellular organization ..............................................................................15 Figure 5: Bioactive lipids metabolism. ..............................................................................41 Figure 6: ER stress and UPR. ............................................................................................61 Figure 7: Loss of 12/15-LO reduces diabetes-induced ER stress in mouse retina ............72 Figure 8: 15-HETE induces ER stress in HRECs ..............................................................74 Figure 9: ER stress induction triggers endothelial leukocyte adhesion in HRECs, while ER stress inhibition abrogates 15-HETE-induced leukocyte adhesion .............................76 Figure 10: Crosstalk between NADPH oxidase and ER stress in 15-HETE-treated HRECs .............................................................................................78 Figure 11: Nox2 deletion has no effect on 12-HETE-induced ER stress in vivo ..............80 Figure 12: 15-HETE induces intracellular Ca2+ release in HRECs ...................................82 Figure 13: ER stress inhibition attenuates 15-HETE-induced VEGFR2 phosphorylation.................................................................................................................84 Figure 14: A graphical summary .......................................................................................92 Table 1. List of abbreviations Abbreviation Term AA Arachidonic acid AMD Age related macular degeneration ATF Activating transcription factor BRB Blood retinal barrier CNV Choroidal neovascularization COX Cyclooxygenase
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