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研究生:呂欣穎
研究生(外文):Hsin-Ying Lu
論文名稱:二基胜肽酶在腹主動脈瘤生長與發展中的角色
論文名稱(外文):The roles of dipeptidyl peptidase-4 in the development and progression of abdominal aortic aneurysm
指導教授:施俊哲施俊哲引用關係
指導教授(外文):Chun-Che Shih
學位類別:博士
校院名稱:國立陽明大學
系所名稱:臨床醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:101
中文關鍵詞:腹主動脈瘤、二基胜肽酶-4、巨噬細胞、胰高血糖素樣肽-1
外文關鍵詞:Abdominal aortic aneurysmDipeptidyl peptidase-4MacrophageGlucagon-like peptide-1
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腹主動脈瘤危及將近10%老年人的生命。除了接受手術治療外,沒有藥物可以有效的治療腹主動脈瘤。而腹主動脈瘤的機轉目前仍不清楚,已被了解的特徵是因淋巴球細胞和巨噬細胞浸潤到血管壁的中外層,造成彈力纖維和膠原蛋白的破壞所致。慢性血管發炎已被證實是影響腹主動脈瘤的重要指標。因浸潤的單核球細胞和巨噬細胞分泌了破壞血管壁完整性和細胞外基質的酵素,因而導致腹主動脈瘤的生成、惡化,甚至破裂。
二基胜肽酶-4,也被稱為淋巴細胞的細胞表面標記 CD26,具有複雜的生物作用,包括細胞內信號傳導,細胞與細胞間的相互作用和酵素活性的功能。二基胜肽酶-4在許多疾病中扮演重要的角色,包括癌症、糖尿病、動脈硬化和一些自體免疫疾病。然而二基生肽酶-4在腹主動脈瘤的角色卻是末知的。
二基胜肽酶-4所表現的總量和活性,甚至於在膜上的表現,都會因不同的生理或病理狀態而有所不同。本研究顯示隨著腹主動脈瘤的生長,血漿中的二基胜肽酶-4的相對活性有顯著的增加,而二基胜肽酶-4抑制劑-佳糖維可以刺激胰高血糖素樣肽-1改善腹主動脈瘤的形成。此外,表現在單核球細胞膜上的CD26,腹主動脈瘤的病患比起控制組有顯著的減少,且這樣的減少和腹主動脈瘤的大小有正相關。這結果與單核球細胞分化成巨噬細胞有關聯。
從基礎研究到臨床證據,本研究證明了具有多功能的二基胜肽酶-4在腹主動脈瘤中是為一重要角色。

Abdominal aortic aneurysm (AAA) is a life-threatening situation affecting almost 10% of elders. There has been no effective medication for AAA other than surgical intervention. Still unclear the mechanism of AAA, the current literature suggests that AAA is characterized by the destruction of elastin and collagen in the media and adventitia via the infiltration of lymphocytes and macrophages. It has been indicated that chronic vascular inflammation is a hallmark of AAA. The main source of proteases from the infiltrated monocytes and macrophages into the vessel wall destroy the integrity of the aortic wall and degrade extracellular matrix (ECM), thus contributing to the development, progression and rupture of AAA.
Dipeptidyl peptidase-4 (DPP-4), also known as lymphocyte cell surface marker CD26, has complex biological roles, including cell membrane associated activation of intracellular signal transduction pathways, cell-to-cell interaction, and enzymatic activity. DPP-4 plays an important role in various diseases, such as cancer, diabetes, atherosclerosis and some autoimmune diseases. The role of DPP-4, however, in AAA is unknown.
The expression of the levels and enzymatic activity of DPP-4, even membrane-bond DPP-4, depends on the specific physiological or pathophysiological processes involved. This study showed that the relative intensity of DPP-4 in plasma significantly increased as AAA growth, which can be attenuated by the DPP-4 inhibitor, sitagliptin, via glucagon-like peptide-1 (GLP-1) action. Furthermore, the membrane-bond expression of CD26 on monocyte population significantly decreased in relation to aneurysm growth compared with control subjects, associating with monocyte-macrophage differentiation.
From experimental study to clinical evidence, this study demonstrated that the multifunctional DPP-4 contributes an important role in AAA progression and development.

誌謝 I
目錄 II
Figure Legends IV
List of Tables V
中文摘要 VI
英文摘要 VII
Abbreviations IX
Chapter 1. Introduction 1
1.1 Definition of abdominal aortic aneurysm (AAA) 2
1.2 Epidemiology of AAA 2
1.3 Risk factors for AAA 2
1.4 Pathobiology of AAA 4
1.5 Management of AAA 6
1.6 Animal models of AAA 9
1.7 Dipeptidyl peptidase-4 (DPP-4) 10
1.8 Physiologic function of DPP-4 10
1.9 Pharmacology of DPP-4 inhibitors 12
1.10 The roles of CD26/DPP-4 and its inhibition in human diseases 13
1.11 Hypothesis and specific aims 16
Chapter 2. Materials and methods 18
2.1 Animal preparation and drugs administration 19
2.2 Measurement of blood pressure 19
2.3 Biochemical measurements 20
2.4 Characteristics and quantification of AAA 20
2.5 Histological and immunofluorescent staining 21
2.6 Terminal deoxynucleotidyl transferase dUTP nick end labeling assay 21
2.7 Gelatin zymography 22
2.8 Cell culture 22
2.9 Measurement of intracellular generation of reactive oxygen species (ROS) 22
2.10 Macrophage chemotaxis assay 23
2.11 Inclusion of patients and the collection of blood samples 23
2.12 Flow cytometry analysis 24
2.13 Monocyte-macrophage differentiation 24
2.14 Knockdown of DPP-4 gene expression by RNA interference 25
2.15 Wright staining 25
2.16 Western blot analysis 26
2.17 Protein array 26
2.18 Statistical analysis 27
Chapter 3. Dipeptidyl peptidase-4 inhibitor decreases abdominal aortic aneurysm formation through GLP-1-dependent monocytic activity in mice 28
3.1 Introduction 29
3.2 Results 30
3.3 Discussion 38
Chapter 4. A potential contribution of dipeptidyl peptidase-4 via the mediation of monocyte differentiation in the development and progression of abdominal aortic aneurysms 43
4.1 Introduction 44
4.2 Results 45
4.3 Discussion 49
Chapter 5. General discussion and conclusions 54
Chapter 6. Perspectives 58
References 60
Appendix I 95

Figure Legends
Figure 1. Sitagliptin attenuated AAA formation in Ang II-infused apoE-/- mice 76
Figure 2. Sitagliptin ameliorated Ang II-induced morphological and biochemical changes in the aortic wall. 77
Figure 3. Sitagliptin suppressed macrophage infiltration in Ang II-infused apoE-/- mice 78
Figure 4. Sitagliptin suppressed gelatinase activity in Ang II-infused apoE-/- mice 79
Figure 5. Treatment with sitagliptin suppresses apoptosis in Ang II-infused apoE-/- mice 80
Figure 6. Liraglutide reduced AAA formation in Ang II-infused apoE-/- mice. 81
Figure 7. GLP-1 decreased ROS generation, migration, and MMPs activity in monocytic cells by Ang II stimulation 82
Figure 8. Sitagliptin did not affect TIMPs expression in Ang II-infused apoE-/- mice 83
Figure 9. The CD26 expression altered in the monocyte population but not in CD4+ lymphocyte population in AAA 84
Figure 10. DPP-4 participated the differentiation of monocytes into macrophages 85
Figure 11. DPP-4 regulated monocytes-macrophages differentiation via P21-ERK1/2 pathway, involving in cytoskeleton activation 86
Figure 12. Protein array analysis associated with AAA 87
Figure 13. Increased macrophages infiltration but decreased DPP-4 expression with an AAA growth in mice aortic specimen 88

List of Tables
Table 1. Effects of daily sitagliptin and Ang II on physiological and biochemical characteristics 89
Table 2. The alternation of DPP-4 substrate by daily sitagliptin administration 90
Table 3. The characteristics of liraglutide-administrated Ang II-induced apoE-/- mice 91
Table 4. The charges of aortic diameters in liraglutide-administrated Ang II-induced apoE-/- mice 92
Table 5. Demographic characteristics of control subjects and AAA patients 93
Table 6. The alternation of biological DPP-4 and GLP-1 in plasma correlation with diameter in AAA 94


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