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系統識別號 U0026-0409201221542600
論文名稱(中文) 動脈硬化中離胺基氧化酶和細胞外基質的交互作用
論文名稱(英文) Interplay between lysyl oxidase and extracellualr matrix homeostasis in arterial stiffness
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 100
學期 2
出版年 101
研究生(中文) 張育慈
研究生(英文) Yu-Tzu Chang
學號 S96991025
學位類別 碩士
語文別 英文
論文頁數 58頁
口試委員 指導教授-蔡曜聲
口試委員-蔡佩珍
口試委員-吳華林
口試委員-江美治
中文關鍵字 動脈硬化  離胺基氧化酶  血管收縮素II  血管旁脂肪 
英文關鍵字 Aortic stiffness  Lysyl oxidase  Angiotensin II  PVAT 
學科別分類
中文摘要 肥胖是造成中風,心肌梗塞,心臟衰竭…等這些心血管疾病的危險因子。之前的研究指出,利用脈波傳導速度當作動脈硬化的指標,發現肥胖的病人脈波傳導速度是明顯增加的,表示肥胖的病人發生動脈硬化的機率是增加的。但是對於為什麼肥胖引起動脈硬化的機制目前還尚未清楚。彈性蛋白和膠原蛋白是在血管中影響動脈的彈性以及硬度的蛋白質,而要使這兩種蛋白質具有正常功能則需要離胺基氧化酶的催化。在我們之前的研究中發現,有基因缺陷導致肥胖的老鼠中離胺基氧化酶是明顯下降的,但是目前我們對於為什麼離胺基氧化酶會下降的原因還不清楚。並且我們觀察到在肥胖的老鼠中,其血管旁脂肪組織明顯的比起正常的老鼠厚。在之前的文獻指出血管旁的脂肪細胞可以利用旁分泌來調控血管的功能。因此,我們假設在肥胖老鼠中,血管旁的脂肪組織所分泌出來的物質會使離胺基氧化酶下降,導致細胞外基質平衡受到破壞,進而使動脈硬化的發生。首先,我們用膠原蛋白膠收縮分析法可以知道利用離胺基氧化酶的抑制劑BAPN降低離胺基氧化酶的活性會導致膠原蛋白膠的縮小。接下來我們在老鼠上給予BAPN以觀察是否會有動脈硬化的發生。我們發現高濃度的BAPN會導致動脈硬化並且增加彈性蛋白的斷點。接下來,我們探討在血管發生結構重塑的過程中離胺基氧化酶所扮演的角色,我們給予同時給予血管收縮素和BAPN。抑制離胺基氧化酶會導致更嚴重的血管重塑以及造成動脈硬化和血管瘤的發生。接下來我們探討,脂肪細胞和血管旁的脂肪細胞所分泌的物質是否會影響到血管平滑肌細胞離胺基氧化酶的活性。因此我們在血管平滑肌細胞上給予3T3-L1所分化的脂肪細胞以及從肥胖老鼠的血管旁脂肪所收集下來的培養液。發現脂肪細胞所分泌的物質會降低離胺基氧化酶的活性。我們也發現給予腫瘤壞死因子增加發炎反應以及雙氧水增加氧化壓力後發現離胺基氧化酶的活性也明顯地被抑制。從我們的結果可以發現在肥胖的老鼠中,血管旁細胞所分泌的物質可能是造成離胺基氧化酶活性下降的原因,因此破壞了細胞外基質的平衡,造成動脈硬化的發生。
英文摘要 Obesity is a significantly independent predictor of cardiovascular risk factor, including stroke, myocardial infarction, heart failure, and overall mortality. Recently, it has been reported that aortic stiffness, reflected by increasing pulse wave velocity (PWV), is increased in obesity. However, the mechanism of obesity-induced aortic stiffness is still unclear. Two main extracellular proteins, collagen and elastin, regulate vascular stability and compliance. However, the function of collagen and elastin are dependent on catalytic activity of lysyl oxidase (LOX). While we have shown that LOX was downregulated in obese ob/ob mice, the mechanism underlying this phenomenon remains unclear. We also observed that the aorta of ob/ob mice is surrounded by abundant perivascular adipose tissue (PVAT). It has been reported that PVAT regulates vascular function through paracrine effects. Therefore, we hypothesized that LOX downregulation, caused by the factors secreted from PVAT, leads to aortic stiffening in obese mice. To test this hypothesis, we used collagen gel contraction assay to determine whether downregulation of LOX by BAPN affected cross-linking. We found that inhibition of LOX activity led to smaller collagen gel. To investigate whether downregulation of LOX triggered aortic stiffness, we administrated mice with BAPN. We found that high dose of BAPN (300, and 600 mg/kg/day) induced aortic stiffness and elastin fragmentation in mice. Furthermore, to verify the role of LOX during aortic remodeling, we administrated BAPN under infusion of angiotensin II. Short-term treatment with BAPN alone (3 weeks) or angiotensin II alone (4 weeks) did not induce aortic stiffness. However, co-treatment of BAPN and angiotensin II increased aortic stiffening and the incidence of aneurysm. Therefore, these results suggested that BAPN promoted angiotensin II-induced aortic remodeling and stiffening. We further studied whether adipocyte-secreted factors downregulated LOX activity. Vascular smooth muscle cells (VSMCs) were treated with conditioned medium that collected from PVAT of ob/ob mice and differentiated 3T3-L1 adipocytes. We found that treatment of 3T3-L1 adipocytes and PVAT conditioned medium significantly downregulated LOX activity in a dose-dependent manner. Finally, we found that LOX activity was significantly decreased in VSMCs by treating them with TNF-α and H2O2. These data suggest that downregulation of LOX, possibly through paracrine effect of PVAT, impaired extracellular matrix homeostasis and triggered aortic stiffness in ob/ob mice
論文目次 INTRODUCTION 1
Structure of aorta 1
Aortic stiffness 2
Collagen and elastin 2
Perivascular adipose tissue (PVAT) 3
Lysyl oxidase 4
Role of LOX in diseases 5
β-aminopropionitrile (BAPN) 5
Angiotensin II in vascular disease 6
Significance 7
MATERIAL AND METHOD 8
Culture of A7r5 8
Culture of 3T3-L1 8
Differentiation of 3T3-L1 8
Collection of 3T3-L1 conditioned medium and treatment of A7r5 9
Collection of PVAT conditioned medium 9
Freezing cells 9
LOX activity 10
Collagen gel 10
Protein extraction 11
Western blot 11
Administration of β-aminopropionitrile (BAPN) 11
Measurement of pulse wave velocity 12
Measurement of blood pressure 12
Elastolytic activity 13
Tissue harvesting 13
Histology and elastic fiber stain 13
Data analysis 14
RESULT 15
Inhibition of LOX affected extracellular matrix cross-linking 15
Downregulation of LOX activity induced aortic stiffness 15
BAPN triggered elastin fragmentation and media thickening 17
BAPN promoted angiotensin II–induced aortic remodeling and stiffening 18
Co-treatment of BAPN and angiotensin II triggered media thickening 19
Adipocyte-secreted factors downregulated LOX activity in the vascular smooth muscle cell 19
Inflammatory cytokine and ROS reduced LOX activity in vascular smooth muscle cell 20
DISCUSSION 22
REFERENCE 30
FIGURE 40
Figure 1. Downregulation of LOX activity led to smaller collagen gel. 40
Figure2. Administration of low dose BAPN did not triggered aortic stiffness. 41
Figure 3. Long-term administration of high dose of BAPN triggered aortic stiffness. 42
Figure 4. BAPN did not affect the synthesis of extracellular matrix proteins. 43
Figure 5. Downregulation of LOX did not affect the thoracic aorta. 45
Figure 6. BAPN triggered elastin fragmentation in the thoracic aorta. 46
Figure 7. BAPN did not affect collagen content in the thoracic aorta. 47
Figure 8. Inhibition of LOX significantly affected the abdominal aorta. 49
Figure 9. BAPN triggered elastin fragmentation in abdominal aorta. 50
Figure 10. BAPN did not induce collagen content in the abdominal aorta. 51
Figure 11. The group of Angiotensin II alone and co-treatment did not increase blood pressure 52
Figure 12. BAPN promoted angiotensin II-induced aortic remodeling. 53
Figure 13. BAPN promoted angiotensin II-induced aortic aneurysm. 54
Fig 14. Co-treatment with BAPN and angiotensin II appeared not to affect the thoracic aorta. 55
Fig 15. Co-treatment with BAPN and angiotensin II increased aortic wall area in abdominal aortas. 56
Figure 16. The factors secreted from differentiated 3T3-L1 adipocyte and PVAT downregulated LOX activity in A7r5 VSMC and led to smaller collagen gel. 57
Figure 17. TNF-α and H2O2 downregulated LOX activity of A7r5. 58
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