博碩士論文 982404010 詳細資訊




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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
參考文獻 References
[1] C.Langston, “Managing Fluid and Electrolyte Disorders in Renal Failure,” Veterinary Clinics of North America - Small Animal Practice, vol. 38, no. 3. pp. 677–697, 2008.
[2] W.-C.Yang andS.-J.Hwang, “Incidence, prevalence and mortality trends of dialysis end-stage renal disease in Taiwan from 1990 to 2001: the impact of national health insurance.,” Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, vol. 23, no. 12, pp. 3977–82, 2008.
[3] D. O. F.Ckd andN.Graded, “Chapter 1: Definition and classification of CKD,” Kidney International Supplements, vol. 3, no. 1, pp. 19–62, 2013.
[4] M. J.Sarnak, A. S.Levey, A. C.Schoolwerth, J.Coresh, B.Culleton, L. L.Hamm, P. A.McCullough, B. L.Kasiske, E.Kelepouris, M. J.Klag, P.Parfrey, M.Pfeffer, L.Raij, D. J.Spinosa, andP. W.Wilson, “Kidney Disease as a Risk Factor for Development of Cardiovascular Disease: A Statement From the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention,” Circulation, vol. 108, no. 17. pp. 2154–2169, 2003.
[5] M.Mallappallil, E. A.Friedman, B. G.Delano, S. I.McFarlane, andM. O.Salifu, “Chronic kidney disease in the elderly: evaluation and management,” Clin Pract (Lond), vol. 11, no. 5, pp. 525–535, 2014.
[6] R.Hajhosseiny, K.Khavandi, andD. J.Goldsmith, “Cardiovascular disease in chronic kidney disease: Untying the Gordian knot,” International Journal of Clinical Practice, vol. 67, no. 1. pp. 14–31, 2013.
[7] F.Verbeke, W.VanBiesen, andR.Vanholder, “The role of collagen metabolism in CKD-associated arterial senescence: Underestimated and underappreciated,” Nephrology Dialysis Transplantation, vol. 26, no. 9, pp. 2726–2728, 2011.
[8] M.Yisireyili, H.Shimizu, S.Saito, A.Enomoto, F.Nishijima, andT.Niwa, “Indoxyl sulfate promotes cardiac fibrosis with enhanced oxidative stress in hypertensive rats,” Life Sciences, vol. 92, no. 24–26, pp. 1180–1185, 2013.
[9] J.Nemcsik, I.Kiss, andA.Tislér, “Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease.,” World journal of nephrology, vol. 1, no. 1, pp. 25–34, 2012.
[10] M.Cecelja andP.Chowienczyk, “Role of arterial stiffness in cardiovascular disease,” JRSM Cardiovascular Disease, vol. 1, no. 4, pp. 1–10, 2012.
[11] S. J. E.Veringa, P. W. B.Nanayakkara, F. J.vanIttersum, I. L.Vegting, C.vanGuldener, Y. M. S. P. M.terWee, andC. D. A.Stehouwer, “Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on arterial compliance and distensibility in patients with mild-to-moderate chronic kidney disease,” Clinical Nephrology, vol. 78, no. 10, pp. 263–272, 2012.
[12] S. C.vanDijk, A. W.Enneman, K. M. A.Swart, J. P.vanWijngaarden, A. C.Ham, E. M.Brouwer-Brolsma, N. L.van derZwaluw, H. J.Blom, E. J.Feskens, J. M.Geleijnse, N. M.vanSchoor, R. A. M.Dhonukshe-Rutten, R. T.deJongh, P.Lips, L. C. P. G. M.deGroot, A. G.Uitterlinden, Y. M.Smulders, A. H.van denMeiracker, F. U. S.Mattace Raso, andN.van derVelde, “Effects of 2-year vitamin B12 and folic acid supplementation in hyperhomocysteinemic elderly on arterial stiffness and cardiovascular outcomes within the B-PROOF trial,” Journal of Hypertension, vol. 33, no. 9, pp. 1897–1906, 2015.
[13] C. H.Liang, C. Y.Yang, K. C.Lu, P.Chu, C. H.Chen, Y. S.Chang, A. P.O’Brien, M.Bloomer, andK. R.Chou, “Factors affecting peritoneal dialysis selection in Taiwanese patients with chronic kidney disease,” Int Nurs Rev, vol. 58, no. 4, pp. 463–469, 2011.
[14] G. A.Beathard, “The Treatment of Vascular Access Graft Dysfunction: A Nephrologist’s View And Experience,” Advances in Renal Replacement Therapy, vol. 1, no. 2, pp. 131–147, 1994.
[15] J.Bergan, G.Schmidt-Schonbein, S.PD, A. N.Nicolaides, M.Boisseau, andB.Eklof, “Chronic Venous Disease,” The New England Journal of Medicine, vol. 355, no. 5, pp. 488–98, 2006.
[16] M. J.Brescia, J. E.Cimino, K.Appel, andB. J.Hurwich, “Chronic Hemodialysis Using Venipuncture and a Surgically Created Arteriovenous Fistula,” New England Journal of Medicine, vol. 275, no. 20, pp. 1089–1092, 1966.
[17] D.Santoro, F.Benedetto, P.Mondello, N.Pipitò, D.Barillà, F.Spinelli, C. A.Ricciardi, V.Cernaro, andM.Buemi, “Vascular access for hemodialysis: Current perspectives,” International Journal of Nephrology and Renovascular Disease, vol. 7. pp. 281–294, 2014.
[18] A.Asif, P.Roy-Chaudhury, andG. A.Beathard, “Early arteriovenous fistula failure: a logical proposal for when and how to intervene.,” Clinical journal of the American Society of Nephrology : CJASN, vol. 1, no. 2. pp. 332–339, 2006.
[19] H. J. T.Huijbregts, M. L.Bots, C. H. A.Wittens, Y. C.Schrama, F. L.Moll, andP. J.Blankestijn, “Hemodialysis arteriovenous fistula patency revisited: Results of a prospective, multicenter initiative,” Clinical Journal of the American Society of Nephrology, vol. 3, no. 3, pp. 714–719, 2008.
[20] J.Malik, M.Slavikova, J.Svobodova, andV.Tuka, “Regular ultrasonographic screening significantly prolongs patency of PTFE grafts,” Kidney International, vol. 67, no. 4, pp. 1554–1558, 2005.
[21] K.Valji, J. J.Bookstein, A. C.Roberts, andG. B.Davis, “Pharmacomechanical thrombolysis and angioplasty in the management of clotted hemodialysis grafts: early and late clinical results.,” Radiology, vol. 178, no. 1, pp. 243–247, 1991.
[22] M.Levi, T.Van DerPoll, andH. R.Büller, “Bidirectional relation between inflammation and coagulation,” Circulation, vol. 109, no. 22. pp. 2698–2704, 2004.
[23] A. Y.Kim, P. L.Walinsky, F. D.Kolodgie, C.Bian, J. L.Sperry, C. B.Deming, E. A.Peck, J. G.Shake, G. B.Ang, R. H.Sohn, C. T.Esmon, R.Virmani, R. S.Stuart, andJ. J.Rade, “Early loss of thrombomodulin expression impairs vein graft thromboresistance: Implications for vein graft failure,” Circulation Research, vol. 90, no. 2, pp. 205–212, 2002.
[24] E. M.Conway andR. D.Rosenberg, “Tumor necrosis factor suppresses transcription of the thrombomodulin gene in endothelial cells.,” Molecular and cellular biology, vol. 8, no. 12, pp. 5588–5592, 1988.
[25] C. J.Chang, Y. S.Ko, P. J.Ko, L. A.Hsu, C. F.Chen, C. W.Yang, T. S.Hsu, andJ. H. S.Pang, “Thrombosed arteriovenous fistula for hemodialysis access is characterized by a marked inflammatory activity,” Kidney International, vol. 68, no. 3, pp. 1312–1319, 2005.
[26] T. C.Rothuizen, C.Wong, P. H. A.Quax, A. J.VanZonneveld, T. J.Rabelink, andJ. I.Rotmans, “Arteriovenous access failure: More than just intimal hyperplasia?,” Nephrology Dialysis Transplantation, vol. 28, no. 5, pp. 1085–1092, 2013.
[27] B. S.Dixon, “Why don’t fistulas mature?,” Kidney International, vol. 70, no. 8. pp. 1413–1422, 2006.
[28] B. C.Liu, L.Li, M.Gao, Y. L.Wang, andJ. R.Yu, “Microinflammation is involved in the dysfunction of arteriovenous fistula in patients with maintenance hemodialysis,” Chinese Medical Journal, vol. 121, no. 21, pp. 2157–2161, 2008.
[29] M. F.Weiss, V.Scivittaro, andJ. M.Anderson, “Oxidative stress and increased expression of growth factors in lesions of failed hemodialysis access,” Am J Kidney Dis, vol. 37, no. 5, pp. 970–980, 2001.
[30] P.Roy-Chaudhury, L. M.Spergel, A.Besarab, A.Asif, andP.Ravani, “Biology of arteriovenous fistula failure,” Journal of Nephrology, vol. 20, no. 2. pp. 150–163, 2007.
[31] J.-J.Chiu andS.Chien, “Effects of Disturbed Flow on Vascular Endothelium: Pathophysiological Basis and Clinical Perspectives,” Physiological Reviews, vol. 91, no. 1, pp. 327–387, 2011.
[32] J. J.Paszkowiak andA.Dardik, “Arterial wall shear stress: observations from the bench to the bedside,” Vascular and Endovascular Surgery, vol. 37, no. 1, pp. 47–57, 2003.
[33] A. M.Malek, G. H.Gibbons, V. J.Dzau, andS.Izumo, “Fluid shear stress differentially modulates expression of genes encoding basic fibroblast growth factor and platelet-derived growth factor B chain in vascular endothelium.,” The Journal of clinical investigation, vol. 92, no. 4, pp. 2013–21, 1993.
[34] J. J.Bergan, G. W.Schmid-Schonbein, P. D.Smith, A. N.Nicolaides, M. R.Boisseau, andB.Eklof, “Chronic venous disease,” N Engl J Med, vol. 355, no. 5, pp. 488–498, 2006.
[35] National Kidney Foundation, “Clinical Practice Guidelines for Vascular Access,” American Journal of Kidney Diseases, vol. 48, no. SUPPL. 1, pp. 487–8, 2006.
[36] F. T.Padberg, K. D.Calligaro, andA. N.Sidawy, “Complications of arteriovenous hemodialysis access: Recognition and management,” Journal of Vascular Surgery, vol. 48, no. 5 SUPPL., 2008.
[37] L.Turmel-Rodrigues, J.Pengloan, S.Baudin, D.Testou, M.Abaza, G.Dahdah, A.Mouton, andD.Blanchard, “Treatment of stenosis and thrombosis in haemodialysis fistulas and grafts by interventional radiology,” Nephrology Dialysis Transplantation, vol. 15, no. 12, pp. 2029–2036, 2000.
[38] S.Sivanesan, T.V.How, R. A.Black, andA.Bakran, “Flow patterns in the radiocephalic arteriovenous fistula: An in vitro study,” Journal of Biomechanics, vol. 32, no. 9, pp. 915–925, 1999.
[39] Y. S. J.Li, J. H.Haga, andS.Chien, “Molecular basis of the effects of shear stress on vascular endothelial cells,” Journal of Biomechanics, vol. 38, no. 10. pp. 1949–1971, 2005.
[40] K.DenChen, Y. S.Li, M.Kim, S.Li, S.Yuan, S.Chien, andJ. Y. J.Shyy, “Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and Shc,” Journal of Biological Chemistry, vol. 274, no. 26, pp. 18393–18400, 1999.
[41] Y. S.Li, J. Y.Shyy, S.Li, J.Lee, B.Su, M.Karin, andS.Chien, “The Ras-JNK pathway is involved in shear-induced gene expression.,” Mol. Cell. Biol., vol. 16, no. 11, pp. 5947–5954, 1996.
[42] Y. J.Shyy, H. J.Hsieh, S.Usami, andS.Chien, “Fluid shear stress induces a biphasic response of human monocyte chemotactic protein 1 gene expression in vascular endothelium.,” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 11, pp. 4678–82, 1994.
[43] L. W.Kraiss, R. L.Geary, E. J. R.Mattsson, S.Vergel, Y. P. T.Au, andA. W.Clowes, “Acute reductions in blood flow and shear stress induce platelet-derived growth factor-a expression in baboon prosthetic grafts,” Circulation Research, vol. 79, no. 1, pp. 45–53, 1996.
[44] X. L.Chen, S. E.Varner, A. S.Rao, J. Y.Grey, S.Thomas, C. K.Cook, M. A.Wasserman, R. M.Medford, A. K.Jaiswal, andC.Kunsch, “Laminar flow induction of antioxidant response element-mediated genes in endothelial cells: A novel anti-inflammatory mechanism,” Journal of Biological Chemistry, vol. 278, no. 2, pp. 703–711, 2003.
[45] D.Pons, F. R.DeVries, P. J.Van DenElsen, B. T.Heijmans, P. H. A.Quax, andJ. W.Jukema, “Epigenetic histone acetylation modifiers in vascular remodelling: New targets for therapy in cardiovascular disease,” European Heart Journal, vol. 30, no. 3. pp. 266–277, 2009.
[46] S. G.Gray andT. J.Ekstrom, “The human histone deacetylase family,” Exp Cell Res, vol. 262, no. 2, pp. 75–83, 2001.
[47] A.Scognamiglio, A.Nebbioso, F.Manzo, S.Valente, A.Mai, andL.Altucci, “HDAC-class II specific inhibition involves HDAC proteasome-dependent degradation mediated by RANBP2,” Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1783, no. 10, pp. 2030–2038, 2008.
[48] B.Zhou, A.Margariti, L.Zeng, andQ.Xu, “Role of histone deacetylases in vascular cell homeostasis and arteriosclerosis,” Cardiovasc Res, vol. 90, no. 3, pp. 413–420, 2011.
[49] X.Kong, M.Fang, P.Li, F.Fang, andY.Xu, “HDAC2 deacetylates class II transactivator and suppresses its activity in macrophages and smooth muscle cells,” Journal of Molecular and Cellular Cardiology, vol. 46, no. 3, pp. 292–299, 2009.
[50] C.Urbich, L.Rössig, D.Kaluza, M.Potente, J. N.Boeckel, A.Knau, F.Diehl, J. G.Geng, W. K.Hofmann, A. M.Zeiher, andS.Dimmeler, “HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells,” Blood, vol. 113, no. 22, pp. 5669–5679, 2009.
[51] L.Zeng, Y.Zhang, S.Chien, X.Liu, andJ. Y. J.Shyy, “The Role of p53 Deacetylation in p21Waf1 Regulation by Laminar Flow,” Journal of Biological Chemistry, vol. 278, no. 27, pp. 24594–24599, 2003.
[52] A.Zampetaki, L.Zeng, A.Margariti, Q.Xiao, H.Li, Z.Zhang, A. E.Pepe, G.Wang, O.Habi, E.Defalco, G.Cockerill, J. C.Mason, Y.Hu, andQ.Xu, “Histone deacetylase 3 is critical in endothelial survival and atherosclerosis development in response to disturbed flow,” Circulation, vol. 121, no. 1, pp. 132–142, 2010.
[53] E.Seto andM.Yoshida, “Erasers of histone acetylation: The histone deacetylase enzymes,” Cold Spring Harbor Perspectives in Biology, vol. 6, no. 4, 2014.
[54] J.Tang, H.Yan, andS.Zhuang, “Histone deacetylases as targets for treatment of multiple diseases.,” Clinical science (London, England : 1979), vol. 124, no. 11, pp. 651–62, 2013.
[55] S.-H.Kang, Y. M.Seok, M.Song, H.-A.Lee, T.Kurz, andI.Kim, “Histone deacetylase inhibition attenuates cardiac hypertrophy and fibrosis through acetylation of mineralocorticoid receptor in spontaneously hypertensive rats.,” Molecular pharmacology, vol. 87, no. 5, pp. 782–91, 2015.
[56] J. L.Hannan, O.Kutlu, B. L.Stopak, X.Liu, F.Castiglione, P.Hedlund, A. L.Burnett, andT. J.Bivalacqua, “Valproic acid prevents penile fibrosis and erectile dysfunction in cavernous nerve-injured rats,” Journal of Sexual Medicine, vol. 11, no. 6, pp. 1442–1451, 2014.
[57] H. C. R.Grunze, “The effectiveness of anticonvulsants in psychiatric disorders,” Dialogues in Clinical Neuroscience, vol. 10, no. 1. pp. 77–89, 2008.
[58] D.-Y.Lee, C.-I.Lee, T.-E.Lin, S. H.Lim, J.Zhou, Y.-C.Tseng, S.Chien, andJ.-J.Chiu, “Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow,” Proceedings of the National Academy of Sciences, vol. 109, no. 6, pp. 1967–1972, 2012.
[59] M. S.Lemson, J. H. M.Tordoir, M. J. A. P.Daemen, andP. J. E. H. M.Kitslaar, “Intimal hyperplasia in vascular grafts,” European Journal of Vascular and Endovascular Surgery, vol. 19, no. 4. pp. 336–350, 2000.
[60] S. D.Patel, M.Waltham, A.Wadoodi, K. G.Burnand, andA.Smith, “The role of endothelial cells and their progenitors in intimal hyperplasia,” Therapeutic Advances in Cardiovascular Disease, vol. 4, no. 2. pp. 129–141, 2010.
[61] B.Ene-Iordache andA.Remuzzi, “Disturbed flow in radial-cephalic arteriovenous fistulae for haemodialysis: Low and oscillating shear stress locates the sites of stenosis,” Nephrology Dialysis Transplantation, vol. 27, no. 1, pp. 358–368, 2012.
[62] C. D.Owens, N.Wake, J. M.Kim, D.Hentschel, M. S.Conte, andA.Schanzer, “Endothelial function predicts positive arterial-venous fistula remodeling in subjects with stage IV and V chronic kidney disease.,” The journal of vascular access, vol. 11, no. 4, pp. 329–334, 2011.
[63] L.Li, C. M.Terry, Y. T. E.Shiu, andA. K.Cheung, “Neointimal hyperplasia associated with synthetic hemodialysis grafts,” Kidney International, vol. 74, no. 10. pp. 1247–1261, 2008.
[64] U. M.Balaguru, L.Sundaresan, J.Manivannan, R.Majunathan, K.Mani, A.Swaminathan, S.Venkatesan, D.Kasiviswanathan, andS.Chatterjee, “Disturbed flow mediated modulation of shear forces on endothelial plane: A proposed model for studying endothelium around atherosclerotic plaques,” Scientific Reports, vol. 6, 2016.
[65] M.Moradzadeh, A.Tabarraei, andH. R.Sadeghnia, “The Role of Histone Deacetylase (HDAC) as a Biomarker in Cancer,” Journal of Molecular Biomarkers & Diagnosis, vol. 06, no. 04, 2015.
[66] M. Y.Ahn, J. H.Jung, Y. J.Na, andH. S.Kim, “A natural histone deacetylase inhibitor, Psammaplin A, induces cell cycle arrest and apoptosis in human endometrial cancer cells,” Gynecologic Oncology, vol. 108, no. 1, pp. 27–33, 2008.
[67] M.Haberland, R. L.Montgomery, andE. N.Olson, “The many roles of histone deacetylases in development and physiology: Implications for disease and therapy,” Nature Reviews Genetics, vol. 10, no. 1. pp. 32–42, 2009.
[68] Y.Jeong, R.Du, X.Zhu, S.Yin, J.Wang, H.Cui, W.Cao, andC. J.Lowenstein, “Histone deacetylase isoforms regulate innate immune responses by deacetylating mitogen-activated protein kinase phosphatase-1,” Journal of Leukocyte Biology, vol. 95, no. 4, pp. 651–659, 2014.
[69] S.Song, S. W.Kang, andC.Choi, “Trichostatin A enhances proliferation and migration of vascular smooth muscle cells by downregulating thioredoxin 1,” Cardiovascular Research, vol. 85, no. 1, pp. 241–249, 2010.
[70] W.Wang, C. H.Ha, B. S.Jhun, C.Wong, M. K.Jain, andZ. G.Jin, “Fluid shear stress stimulates phosphorylation-dependent nuclear export of HDAC5 and mediates expression of KLF2 and eNOS,” Blood, vol. 115, no. 14, pp. 2971–2979, 2010.
[71] Z.Lin, “Kruppel-Like Factor 2 (KLF2) Regulates Endothelial Thrombotic Function,” Circulation Research, vol. 96, no. 5, pp. e48–e57, 2005.
[72] M. A.Alaiti, G.Orasanu, D.Tugal, Y.Lu, andM. K.Jain, “Kruppel-like factors and vascular inflammation: Implications for atherosclerosis,” Current Atherosclerosis Reports, vol. 14, no. 5, pp. 438–449, 2012.
[73] P.Novodvorsky andT. J. A.Chico, “Chapter Seven - The Role of the Transcription Factor KLF2 in Vascular Development and Disease,” in Genetics of Cardiovascular Disease, vol. Volume 124, 2014, pp. 155–188.
[74] L.Nayak, Z.Lin, andM. K.Jain, “‘Go with the flow’: how Krüppel-like factor 2 regulates the vasoprotective effects of shear stress.,” Antioxidants & redox signaling, vol. 15, no. 5, pp. 1449–61, 2011.
[75] I.-S.Kwon, W.Wang, S.Xu, andZ.-G.Jin, “Histone deacetylase 5 interacts with Kruppel-like factor 2 and inhibits its transcriptional activity in endothelium.,” Cardiovascular research, vol. 104, no. 1, pp. 127–137, 2014.
[76] E.DiGiorgio, A.Clocchiatti, S.Piccinin, A.Sgorbissa, G.Viviani, P.Peruzzo, S.Romeo, S.Rossi, A. P.Dei Tos, R.Maestro, andC.Brancolini, “MEF2 is a converging hub for HDAC4 and PI3K/Akt-induced transformation.,” Molecular and cellular biology, no. September, 2013.
[77] R.Janardhanan, B.Yang, P.Vohra, B.Roy, S.Withers, S.Bhattacharya, J.Mandrekar, H.Kong, E. B.Leof, D.Mukhopadhyay, andS.Misra, “Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model,” Kidney International, vol. 84, no. 2, pp. 338–352, 2013.
[78] M.Righetti, G.Ferrario, P.Serbelloni, S.Milani, andA.Tommasi, “Some Old Drugs Improve Late Primary Patency Rate of Native Arteriovenous Fistulas in Hemodialysis Patients,” Annals of Vascular Surgery, vol. 23, no. 4, pp. 491–497, 2009.
[79] R.Pisoni, J.Barker-Finkel, andM.Allo, “Statin therapy is not associated with improved vascular access outcomes.,” Clinical journal of the American Society of Nephrology : CJASN, vol. 5, no. 8, pp. 1447–50, 2010.
[80] D. M.Herrington, E.Vittinghoff, F.Lin, J.Fong, F.Harris, D.Hunninghake, V.Bittner, H. G.Schrott, R. S.Blumenthal, andR.Levy, “Statin therapy, cardiovascular events, and total mortality in the Heart and Estrogen/progestin Replacement Study (HERS),” Circulation, vol. 105, no. 25, pp. 2962–2967, 2002.
[81] N.Birch, J.Fillaus, andM. C.Florescu, “The effect of statin therapy on the formation of arteriovenous fistula stenoses and the rate of reoccurrence of previously treated stenoses,” Hemodialysis International, vol. 17, no. 4, pp. 586–593, 2013.
[82] B.Ene-Iordache, L.Cattaneo, G.Dubini, andA.Remuzzi, “Effect of anastomosis angle on the localization of disturbed flow in ‘side-to-end’ fistulae for haemodialysis access,” Nephrology Dialysis Transplantation, vol. 28, no. 4, pp. 997–1005, 2013.
[83] J. E.Hull, B.V.Balakin, B. M.Kellerman, andD. K.Wrolstad, “Computational fluid dynamic evaluation of the side-to-side anastomosis for arteriovenous fistula,” Journal of Vascular Surgery, vol. 58, no. 1, 2013.
[84] E.Rajabi-Jagahrgh, M. K.Krishnamoorthy, P.Roy-Chaudhury, P.Succop, Y.Wang, A.Choe, andR. K.Banerjee, “Longitudinal assessment of hemodynamic endpoints in predicting arteriovenous fistula maturation,” Seminars in Dialysis, vol. 26, no. 2, pp. 208–215, 2013.
[85] M.Mottamal, S.Zheng, T. L.Huang, andG.Wang, “Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents,” Molecules, vol. 20, no. 3. pp. 3898–3941, 2015.
[86] J. M.López-Novoa, A. B.Rodríguez-Peña, A.Ortiz, C.Martínez-Salgado, andF. J.López Hernández, “Etiopathology of chronic tubular, glomerular and renovascular nephropathies: Clinical implications,” Journal of Translational Medicine, vol. 9, no. 1, p. 13, 2011.
[87] J. P.Cardinale, S.Sriramula, R.Pariaut, A.Guggilam, N.Mariappan, C. M.Elks, andJ.Francis, “HDAC inhibition attenuates inflammatory, hypertrophic, and hypertensive responses in spontaneously hypertensive rats,” Hypertension, vol. 56, no. 3, pp. 437–444, 2010.
[88] S.Khan, G.Jena, andK.Tikoo, “Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat,” Experimental and Molecular Pathology, vol. 98, no. 2, pp. 230–239, 2015.
[89] I.Mannaerts, N. R.Nuytten, V.Rogiers, K.Vanderkerken, L. avanGrunsven, andA.Geerts, “Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vivo.,” Hepatology (Baltimore, Md.), vol. 51, no. 2, pp. 603–14, 2010.
[90] G.Kang, Y. R.Lee, H. K.Joo, M. S.Park, C. S.Kim, S.Choi, andB. H.Jeon, “Trichostatin a modulates angiotensin II-induced vasoconstriction and blood pressure via inhibition of p66shc activation,” Korean Journal of Physiology and Pharmacology, vol. 19, no. 5, pp. 467–472, 2015.
[91] W.Lin, Q.Zhang, L.Liu, S.Yin, Z.Liu, andW.Cao, “Klotho restoration via acetylation of Peroxisome Proliferation–Activated Receptor γ reduces the progression of chronic kidney disease,” Kidney International, vol. 92, no. 3, pp. 669–679, 2017.
[92] A.Iyer, A.Fenning, J.Lim, G. T.Le, R. C.Reid, M. A.Halili, D. P.Fairlie, andL.Brown, “Antifibrotic activity of an inhibitor of histone deacetylases in DOCA-salt hypertensive rats: Research paper,” British Journal of Pharmacology, vol. 159, no. 7, pp. 1408–1417, 2010.
[93] J.Choi, S.Park, T. K.Kwon, S. I.Sohn, K. M.Park, andJ. I.Kim, “Role of the histone deacetylase inhibitor valproic acid in high-fat diet-induced hypertension via inhibition of HDAC1/angiotensin II axis,” International Journal of Obesity, vol. 41, no. 11, pp. 1702–1709, 2017.
[94] M.Pang, L.Ma, N.Liu, M.Ponnusamy, T. C.Zhao, H.Yan, andS.Zhuang, “Histone deacetylase 1/2 mediates proliferation of renal interstitial fibroblasts and expression of cell cycle proteins,” Journal of Cellular Biochemistry, vol. 112, no. 8, pp. 2138–2148, 2011.
[95] M.Pang andS.Zhuang, “Histone deacetylase: a potential therapeutic target for fibrotic disorders.,” The Journal of pharmacology and experimental therapeutics, vol. 335, no. 2, pp. 266–72, 2010.
[96] P.Soderland, S.Lovekar, D. E.Weiner, D. R.Brooks, andJ. S.Kaufman, “Chronic Kidney Disease Associated With Environmental Toxins and Exposures,” Advances in Chronic Kidney Disease, vol. 17, no. 3. pp. 254–264, 2010.
[97] R. X.Li, W. H.Yiu, andS. C. W.Tang, “Role of bone morphogenetic protein-7 in renal fibrosis,” Frontiers in Physiology, vol. 6, 2015.
[98] N.Liu, S.He, L.Ma, M.Ponnusamy, J.Tang, E.Tolbert, G.Bayliss, T. C.Zhao, H.Yan, andS.Zhuang, “Blocking the Class I Histone Deacetylase Ameliorates Renal Fibrosis and Inhibits Renal Fibroblast Activation via Modulating TGF-Beta and EGFR Signaling,” PLoS ONE, vol. 8, no. 1, 2013.
[99] K.VanBeneden, C.Geers, M.Pauwels, I.Mannaerts, D.Verbeelen, L. avanGrunsven, andC.Van denBranden, “Valproic acid attenuates proteinuria and kidney injury.,” Journal of the American Society of Nephrology : JASN, vol. 22, no. 10, pp. 1863–75, 2011.
[100] J. K.Ryu, W. J.Kim, M. J.Choi, J. M.Park, K. M.Song, M. H.Kwon, N. D.Das, K. D.Kwon, D.Batbold, G. N.Yin, andJ. K.Suh, “Inhibition of histone deacetylase 2 mitigates profibrotic TGF-??1 responses in fibroblasts derived from Peyronie’s plaque,” Asian Journal of Andrology, vol. 15, no. 5, pp. 640–645, 2013.
[101] S.Yoon andG. H.Eom, “HDAC and HDAC Inhibitor: From Cancer to Cardiovascular Diseases,” Chonnam Medical Journal, vol. 52, no. 1, p. 1, 2016.
[102] J. Z.Xinming Luo, Ming Zhang, Liying Deng, “Effects of valproate on the carotid artery intima-media thickness in epileptics,” Indian J Pharmacol, vol. 47, pp. 45–48, 2015.
[103] T.Azechi, D.Kanehira, T.Kobayashi, R.Sudo, A.Nishimura, F.Sato, andH.Wachi, “Trichostatin A, an HDAC class I/II inhibitor, promotes Pi-induced vascular calcification via up-regulation of the expression of alkaline phosphatase.,” Journal of atherosclerosis and thrombosis, vol. 20, no. 6, pp. 538–547, 2013.
[104] X.-Y.Dai, M.-M.Zhao, Y.Cai, Q.-C.Guan, Y.Zhao, Y.Guan, W.Kong, W.-G.Zhu, M.-J.Xu, andX.Wang, “Phosphate-induced autophagy counteracts vascular calcification by reducing matrix vesicle release,” Kidney International, vol. 83, no. 6, pp. 1042–1051, 2013.
[105] J. H.Choi, K. H.Nam, J.Kim, M. W.Baek, J. E.Park, H. Y.Park, H. J.Kwon, O. S.Kwon, D. Y.Kim, andG. T.Oh, “Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 11, pp. 2404–2409, 2005.
[106] Clin J Am Soc Nephrol. “New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes. ” Clinical Journal of the American Society of Nephrology, vol. 11, no. 8, pp. 1504-1512, 2016.

[107] Berardi DE1, Tarbell JM. “Stretch and Shear Interactions Affect Intercellular Junction Protein Expression and Turnover in Endothelial Cells. ” Cellular and Molecular Bioengineering, vol. 2, no. 3, pp. 320-331, 2009.
[108] Harikrishnan KN1, Karagiannis TC, Chow MZ, El-Osta A. “Effect of valproic acid on radiation-induced DNA damage in euchromatic and heterochromatic compartments. ” Cell Cycle, vol. 7, no. 4, pp. 468-476, 2008.
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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