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

NCUIR > college of Health Sciences and Technology > Graduate Institute of Life Science > Electronic Thesis & Dissertation > Item 987654321/76764

Please use this identifier to cite or link to this item: http://ir.lib.ncu.edu.tw/handle/987654321/76764

Title:	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
Authors:	楊東霖;Yang, Tung-Lin
Contributors:	生命科學系
Keywords:	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;High and oscillatory shear stress;Histone deacetylase;Autogenous arteriovenous fistula;Chronic kidney disease;Valproic acid;Fibrosis;Intimal hyperplasia;Thrombomodulin
Date:	2018-07-02
Issue Date:	2018-08-31 11:36:53 (UTC+8)
Publisher:	國立中央大學
Abstract:	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。;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.
Appears in Collections:	[Graduate Institute of Life Science] Electronic Thesis & Dissertation

Files in This Item:

File	Description	Size	Format
index.html		0Kb	HTML	244	View/Open

社群 sharing

Loading...