혈관염증질환에서 PTP4A1의 새로운 역할규명 = A Novel Role of Protein Tyrosine Phosphatase (PTP4A1) in Vascular Inflammation

목차 (Table of Contents)

• 국문 초록 i
• ABSTRACT vii
• List of Figures and Tables xvii
• GENERAL INTRODUCTION 1
• I. Vascular Endothelium and Human Diseases 2
• 1. Endothelial Functions 3
• 2. Endothelial Dysfunction 6
• II. Atherosclerosis 10
• 1. Pathophysiology of Atherosclerosis 10
• 2. Regulation of Signaling Pathways in Atherogenesis 13
• 3. Current Therapies for Atherosclerotic Cardiovascular Diseases 17
• III. Aneurysm 19
• 1. Pathophysiology of AAAs 19
• 2. TGF-β signaling 23
• 3. Current Therapies for Abdominal Aortic Aneurysm 25
• IV. Protein Tyrosine Phosphatases 26
• 1. PTP4A 26
• 2. PTM in Signaling Pathway 27
• PART I. AHTROSCEROSIS 29
• Endothelial PTP4A1 mitigates vascular inflammation through USF1/A20 Axis-mediated NF-κB inactivation 29
• I. INTRODUCTION 30
• II. Materials and methods 33
• 1. Experimental animals 33
• 2. Histological analysis 34
• 3. Immuno-staining 35
• 4. Laser capture microdissection assay 36
• 5. Cell culture 36
• 6. Lentivirus production and virus infection 37
• 7. siRNA treatment and transfection 38
• 8. Immunoblot analysis 39
• 9. Quantitative real-time polymerase chain reaction (qRT-PCR) and RT-PCR 40
• 10. Cell adhesion assay 40
• 11. Luciferase reporter gene assay 41
• 12. Chromatin immunoprecipitation (ChIP) assay 42
• 13. Mass spectrometric analysis 42
• III. RESULTS 46
• 1. Down-Regulation of PTP4A1 in Artery Wall during Atherosclerotic Lesion Development 46
• 2. Loss of Endothelial PTP4A1 Accelerates the Inflammatory Responses 48
• 3. PTP4A1 Deficiency Exacerbates the Development of Atherosclerosis in ApoE -/- Mice 56
• 4. PTP4A1 Inhibits the Expression of Adhesion Molecules in Response to Pro-inflammatory Cytokines in Endothelial Cells 67
• 5. Endothelial PTP4A1 Reduces the Development of Atherosclerosis in ApoE -/- Mice 77
• 6. Phosphatase Activity of PTP4A1 is Important to Inhibit Expression of Adhesion Molecules by NF-κB Activation 88
• 8. PTP4A1 Enhances A20 Transcription through the Regulation of USF1 Phosphorylation 102
• IV. DISCUSSION 116
• PART II. Abdominal Aortic Aneurysm (AAA) 125
• Endothelial PTP4A1 alleviate angiotensin II-induced abdominal aortic aneurysm 125
• I. Introduction 126
• II. Materials and methods 129
• 1. Induction of the mouse AAA model and animal studies 129
• 2. Blood pressure (BP) 129
• 3. Histological and immunofluorescence staining 130
• 4. In situ zymography 131
• 5. In situ detection of nitric oxide (NO) 131
• 6. Immunoblotting 132
• 7. Cell culture and virus infection 133
• 8. Quantitative real-time polymerase chain reaction (qRT-PCR) 134
• 9. Statistical analysis 134
• III. RESULTS 136
• 1. Endothelial PTP4A1 Reduced the Development of Abdominal Aortic Aneurysm in Ang II-infused ApoE -/- Mice 136
• 2. Endothelial PTP4A1 Alleviates the Ang II-induced Structural Damages of Aortas 143
• 3. Immature Neovessels and Inflammation in Aneurysmal Lesions Are Inhibited by Endothelial PTP4A1 150
• 4. Endothelial PTP4A1 Prevents Ang II-Induced MMP Activation and Collagen degradation 157
• 5. Increased Level of TGF-β1 by Endothelial PTP4A1 Improves the Vessel Integrity 162
• IV. Discussion 166
• REFERENCES 170
• ACKNOWLEDGMENT 199
• Curriculum Vitae 202