剪力和組織蛋白去乙醯酶在動靜脈廔管失效扮演的角色

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姓名	楊東霖(Tung-Lin Yang) 查詢紙本館藏	畢業系所	生命科學系
論文名稱	剪力和組織蛋白去乙醯酶在動靜脈廔管失效扮演的角色 (Roles of Shear Stress and Histone Deacetylases in Arteriovenous Fistula Failure)
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摘要(中)	血液透析患者的自體動靜脈廔管autogenous arteriovenous fistula (AVF) 失效，在台灣已經成為一個重要的公共健康問題。AVF 是血液透析通路的最佳形式，在台灣廣泛為末期腎病患者洗腎時所使用。但內膜增生而導致血栓、狹窄等問題都可能導致AVF失效。AVF會改變血流動力環境。我們在AVF的吻合部位觀察到高速的振盪剪切應力(high and oscillatory shear stress, HOS)，這可能是內膜增生的原因。過去研究已經表明組蛋白去乙醯酶 (histone deacetylase, HDAC) -1/2/3與流體剪切應力有關，並且調節動脈硬化和內膜增生。HDAC-1/2/3是重要的表觀遺傳調節物，用於介導內皮細胞中的氧化，炎症和增殖反應。因此，本研究調查了HDAC-1/2/3在AVF的作用。我們通過免疫熒光染色，發現HDAC-1/2/3的表達增加於人類和大鼠AVF的吻合部位。我們使用體外流體系統模擬人類AVF的流動模式。發現HOS誘導HDAC-3與KLF2的結合並導致血栓調節蛋白（thrombomodulin, TM）的表達下降。HDAC-3特異性siRNA可抑制HOS誘導的TM表達下降。為了減少AVF的內膜增生，我們以髮夾環型式改變AVF結構來減少擾流。I類特異性HDAC抑製劑丙戊酸 (valproic acid, VPA) 可促進TM的表達及降低大鼠的AVF內膜增生。此外VPA也能抑制I型膠原和纖連蛋白在慢性腎病 (chronic kidney disease, CKD) 大鼠的動脈表達，減少血管纖維化及降低高血壓。總和而言，治療AVF功能障礙可透過物理性和化學性干預措施來進行，我們的研究結果表明AVF特有的HOS會誘發HDAC表達及AVF的內膜增生，改善AVF擾流與開發新藥物都有助於減少AVF失效。髮夾環AVF的流體型態優於傳統的端-側AVF，將是外科在執行AVF 手術時的新選擇。HDAC抑制劑不只能抑制AVF的內膜增生也能減少CKD刺激的血管纖維化及高血壓，顯示HDAC抑制劑在心血管領域的新功能。
摘要(英)	The failure of autogenous arteriovenous fistula (AVF) in hemodialysis patients has become an important public health problem in Taiwan. AVF is the best form of hemodialysis, it is widely used in Taiwan for patients with end-stage kidney disease. However, the problem of intimal hyperplasia, which leads to thrombosis and stenosis, may lead to AVF failure. AVF can change the dynamic environment of blood flow. We observed the high and oscillatory shear stress (HOS) in the anastomotic site of AVF, which may be the cause of intimal hyperplasia. Past studies have shown that histone deacetylase (HDAC) - 1/2/3 are related to shear stress and regulates arteriosclerosis and intimal hyperplasia. HDAC - 1/2/3 are important epigenetic modulators for mediate oxidative, inflammatory and proliferative reactions in endothelial cells. Therefore, this study investigated the role of HDAC-1/2/3 in AVF. We found that the expression of HDAC-1/2/3 in the anastomotic sites of human and rat AVF were increased by immunofluorescence staining. We simulated the flow pattern of human AVF using in vitro flow systems. It was found that HOS induce the binding of HDAC-3 to KLF2 and leads to a down-regulation of thrombomodulin (TM). HDAC-3 specific siRNA can inhibit HOS-induced TM down-regulation. To reduce the intimal hyperplasia of AVF, we changed the AVF structure with "bulb-shaped hairpin loop" to reduce turbulence flow. Class I-specific HDACs inhibitors (HDI) (valproic acid, VPA) can promote TM expression and reduce intimal hyperplasia in rat AVF. In addition, VPA can also inhibit the arterial expression of type I collagen and fibronectin in chronic kidney disease (CKD) rats, reduce vascular fibrosis and lower hypertension. In summary, treatment of AVF dysfunction can be performed through physical and chemical interventions. The results of our research show that the special HOS of AVF can induce HDACs expression and intimal hyperplasia of AVF. Improvement of AVF fluid dynamics and development of new drugs all contribute to reducing AVF failures. The fluid type of the "bulb-shaped hairpin loop" AVF is superior to the traditional end to side AVF, which will be the new choice for surgical operation of AVF. VPA not only inhibit AVF intimal hyperplasia but also reduce CKD-induced vascular fibrosis and hypertension. It shows a new function in the cardiovascular field of HDI.
關鍵字(中)	★ 高速的振盪剪切應力 ★ 組蛋白去乙醯酶 ★ 動靜脈廔管 ★ 慢性腎病 ★ 丙戊酸 ★ 纖維化 ★ 內膜增生 ★ 血栓調節蛋白	關鍵字(英)	★ High and oscillatory shear stress ★ Histone deacetylase ★ Autogenous arteriovenous fistula ★ Chronic kidney disease ★ Valproic acid ★ Fibrosis ★ Intimal hyperplasia ★ Thrombomodulin
論文目次	Table of Content 中文摘要 i Abstract in English ii Acknowledgments iii Table of Content iv List of Table vii List of Figures viii Abbreviation x Chapter I - Introduction 1 I.1 End-Stage Renal Disease (ESRD) and Chronic Kidney Disease (CKD) 1 I.2 Arteriovenous Fistula (AVF) 2 I.3 AVF Failure 3 I.4 Blood Flow and Shear Stress in AVF 4 I.5 Shear Stress and Endothelium Cells 6 I.6 Histone Deacetylases with Cardiovascular Disease 7 I.7 Histone Deacetylases with Tissue Fibrosis 7 I.8 Significance and Novelty 8 Chapter II - Specific Aims 9 II.1 Specific Aims 9 Chapter III - Materials and Methods 10 III.1 Antibodies 10 III.2 Human AVF and CKD Arteries Samples 10 III.3 Rat AVF Model 10 III.4 High-Resolution Ultrasound 11 III.5 Immunofluorescence Staining and Measurement 12 III.6 Morphometric Analysis of Neointimal Formation 12 III.7 Cell Culture 12 III.8 Flow System 12 III.9 Western Blot Analysis 13 III.10 Quantitative Real-Time PCR 13 III.11 Immunoprecipitation 13 III.12 Luciferase Reporter Assay 14 III.13 Chromatin Immunoprecipitation (ChIP) Assay 14 III.14 Rat CKD Model 14 III.15 Masson Staining 15 III.16 Biochemical Values of the Renal Function 15 III.17 Blood Pressure 15 III.18 Statistical Analysis 15 Chapter IV - Results 16 Part A Disturbed Flow Through HDAC-3 Stimulate Intimal Hyperplasia in AVF Failure 16 IV. A1 High and Oscillation Shear Stress and Intimal Hyperplasia in Human AVF Anastomosis Sites 16 IV.A2 High and Oscillation Shear Stress and Intimal Hyperplasia at Rat AVF Anastomosis Sites 16 IV.A3 HOS Induced the Expression and Activation of HDAC-1/2/3 in AVF 17 IV.A4 HOS Regulate TM Expression Through KLF2 18 IV.A5 HOS Induce Binding of HDAC-3 and KLF2 and Increases KLF2 Deacetylation 19 IV.A6 VPA Inhibits HOS-Induced Intimal Hyperplasia in Rat AVF 20 IV.A7 Using the Innovative AVF Structure to Reduce Turbulent Flow and Intimal Hyperplasia 20 Part B The Role of Histone Deacetylases Inhibitor VPA in Arterial Fibrosis 21 IV.B1 CKD Stimulates Arterial Fibrosis in Humans 21 IV.B2 CKD Stimulates Increased Expressions of Type I and III Collagens and Fibronectin in Patients 21 IV.B3 Increased Expression and Activation of HDAC-1/2/3 in Arteries of CKD Rats and their Inhibitions by VPA Administration 22 IV.B4 VPA Inhibits Arterial Fibrosis in CKD Rats 22 IV.B5 VPA Inhibits the Expressions of Arterial Type I Collagen and Fibronectin in CKD Rats 23 IV.B6 VPA cannot Improve Renal Function but can Reduce Blood Pressure in CKD Rats 23 Chapter V - Discussion 25 Part A Disturbed Flow Through HDAC-3 Stimulate Intimal Hyperplasia in AVF Failure 25 Part B The Role of Histone Deacetylases Inhibitor VPA in Arterial Fibrosis 29 Chapter VI - Conclusion 33 References 34 Table 47 Figures 48 Appendix - Supplementary data 93 CFD Simulation of Blood Shear Stress in Rat AVF 93 List of Tables Table 1: Patients’ Baseline Clinical Characteristics and Shear Stress Parameters 47 List of Figures Figure I-1 Vascular Access for Hemodialysis 48 Figure I-2 ECs with Hemodynamic Forces 49 Figure I-3 AVF Failure and Disturbed Flow 50 Figure I-4 Molecular Structures of Valproic Acid (VPA) 51 Figure IV-A1 High and Oscillatory Shear Stresses and Intimal Hyperplasia Expressed at Anastomosis Sites in Human AVF 52 Figure IV-A2 HOS in the Venous Anastomosis Site Induces Intimal Hyperplasia in the Rat AVF Model 55 Figure IV-A3 HOS Induce the Expression and Activation of HDAC-1/2/3 in the EC Layer of Human and Rat AVF 59 Figure IV-A4 HOS Regulate TM Expression Through KLF2 66 Figure IV-A5 HOS Induces HDAC-3 Binding to KLF2 and Increases Acetylation of KLF2 69 Figure IV-A6 VPA Suppresses HOS Induced Neointima Formation in the Rat AVF Model 71 Figure IV-A7 Application of Innovative AVF Structure for Reduction of Turbulent Flow and Intimal Hyperplasia 75 Figure IV-A8 A Schematic Diagram of the Mechanisms Underlying Shear-Modulations in EC HDAC-1/2/3 and TM Expression 80 Figure IV-B1 CKD Induces Arterial Fibrosis in CAD Patients 81 Figure IV-B2 CKD Induces the Expressions of Type I and III Collagens and Fibronectin in Vascular Walls of CAD Patients 82 Figure IV-B3 Increased Expression and Activation of HDAC-1/2/3 in Arteries of CKD Rats and their Inhibition by VPA 84 Figure IV-B4 VPA Administration Significantly Inhibits Arterial Fibrosis in CKD Rats 85 Figure IV-B5 VPA Administration Inhibits CKD Induced Type I Collagen and Fibronectin Expressions in the Vascular Wall of CKD Rats 88 Figure IV-B6 VPA Treatment Decreases Blood Pressure, but does not Affect the Levels of BUN and Creatinine in CKD Rats 92 Supplementary Data: CFD Simulation of Blood Shear Stress in Rat AVF 93
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指導教授	裘正健王健家(Jeng-Jiann Chiu Chien-Chia Wang)	審核日期	2018-7-2
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