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系統識別號 U0026-3008201612545400
論文名稱(中文) 探討靈芝三萜類在小鼠頸動脈結紮模式中防治動脈粥狀硬化之機制
論文名稱(英文) The Atheroprotective Mechanism of Triterpenoids from Ganoderma Tsugae in the Carotid-Artery-Ligation Mouse Model
校院名稱 成功大學
系所名稱(中) 細胞生物與解剖學研究所
系所名稱(英) Institute of Cell Biology and Anatomy
學年度 104
學期 2
出版年 105
研究生(中文) 林詠卿
研究生(英文) Yung-Ching Lin
學號 T96034060
學位類別 碩士
語文別 英文
論文頁數 46頁
口試委員 指導教授-莫凡毅
口試委員-江美治
口試委員-王仰高
中文關鍵字 動脈粥狀硬化  動脈內膜增生  血液紊流  內皮細胞功能失調 
英文關鍵字 atherosclerosis  neointima formation  triterpenoids  disturbed flow  endothelial dysfunction 
學科別分類
中文摘要 動脈粥狀硬化是一慢性發炎性疾病,內膜增生是其中重要的病理特徵。動脈粥狀硬化好發在發生血液紊流的動脈區段。靈芝三萜類(包含多種靈芝酸及靈芝醇)在心臟過度運作的動物模式中可以藉由降低氧化壓力來避免心臟受損。另外,靈芝三萜類在細胞實驗中發現可以降低促進發炎反應的細胞激素來抑制發炎反應。而靈芝三萜類對於動脈粥狀硬化的作用目前還不清楚。我們推測靈芝三萜類可透過抑制發炎反應和氧化壓力來保護動脈免於粥狀硬化。為測試靈芝作用,我們模擬動脈粥狀硬化好發區的血液紊流,在小鼠的總左頸動脈分支處進行結紮術。血管結紮後造成下方近心端的左總頸動脈內血流受阻,流量小並產生往復迴流衝擊。我們發現,不管是每天給予皮下注射300毫克/公斤或是灌食500 毫克/公斤的靈芝三萜類萃取都可以避免結紮14天後動脈內膜增生,也能防止病變區域單核球細胞和活性氧化物的堆積、內皮細胞的凋亡和再生。顯示靈芝三萜類具有保護動脈的效果。血液紊流會造成在血管腔最內層的內皮細胞功能失調,進一步引發動脈粥狀硬化的生成。因此我們接續探討在血液紊流刺激下的內皮細胞功能是否會受靈芝三萜類保護,我們在手術後三天就將小鼠犧牲取其動脈,此階段動脈結構上尚無明顯變化,但已發現在控制組內皮細胞有較高的氧化壓力、單核球趨化蛋白素、內皮素(endothelin)和溫韋伯氏因子(vWF)表現,而皮下注射300毫克/公斤/天靈芝三萜類可有效抑制這些內皮細胞失能危險因子的表現。為了進一步研究靈芝三萜類的抗氧力,我們利用過氧化氫直接在人類臍帶靜脈內皮細胞中製造一個高氧化壓力的環境並同時在培養基中給予300微克/毫升靈芝三萜類,在30分鐘後偵測細胞死亡情形。發現和控制組相比,靈芝三萜類共同處理的組別受高氧化細胞致死率有顯著減少。此外,為測試靈芝三萜類是否具有治療效果,我們在手術後的第三天才給予靈芝三萜類,並持續給予到第14天。結果顯示,術後三天內皮細胞已失能才開始處理靈芝三萜類仍具抑制動脈內皮增生功效,證實了在血液紊流引起的動脈病變當中,靈芝三萜類可以直接的抑制氧化壓力保護內皮細胞功能進而防治動脈病變。
英文摘要 Atherosclerosis is a chronic inflammatory vascular disease and is prone to occur at the sites encountering blood flow turbulence. Neointima formation is a distinct feature of atherosclerosis at the initial stage. Triterpenoid extract from Ganoderma, containing a variety of ganoderic acids and alcohols (GAs), alleviates cardiac injury in a work-overload mouse model through its anti-inflammatory and anti-oxidant activities. However the protective potential of GAs against atherosclerosis was unclear. We hypothesized that GAs may prevent atherosclerosis through its anti-inflammation and anti-oxidant activities. We tested this hypothesis using a complete-carotid-artery-ligation mouse model to create flow turbulence and induce neointima formation. We found that either subcutaneous (300 mg/kg/day) or oral (500 mg/kg/day) GAs treatment significantly inhibited neointima formation 14 days after ligation. We found elevated levels of monocytes/macrophages infiltration, endothelial reactive oxygen species accumulation, apoptosis, and proliferation in the lesion sites 14 days after ligation. GAs treatment prevented the monocytes/macrophages infiltration, endothelial ROS accumulation, apoptosis, and proliferation induced by disturbed flow. The endothelial dysfunction induced by disturbed flow initiates the atherogenesis. Thus, we examined the arterial endothelium 3 days after surgery, while there was still no structural changes being detected. We found that the levels of endothelial oxidative stress, monocyte chemoattractant protein-1, endothelin-1, and von Willebrand factor were up-regulated by disturbed blood flow, and these inductions were blocked by subcutaneous GAs (300 mg/kg/day) treatment. In addition, we tested the therapeutic potential of GAs by delaying the treatment 3 days after surgery. The delayed GAs treatment remained effective in preventing intimal hyperplasia, demonstrating its therapeutic activities on existing vascular conditions. To assess the anti-oxidant activities of GAs, we treated HUVECs with H2O2 in combination with GAs for 30 min. GAs successfully ameliorated the oxidative stress and prevented the cells death induced by H2O2 in HUVECs, indicating that GAs protect arteries against atherosclerosis via restoring endothelial function by their anti-oxidant activities.
論文目次 中文摘要................I
Abstract..................III
Contents..................V
Chapter 1 Introduction...................1
1.1 Ganoderma and Triterpenoids..............1
1.2 Triterpenoids from Ganoderma.............2
1.3 Atherosclerosis...............2
1.4 Endothelial dysfunction..............4
1.4-1 Adhesion molecules.................4
1.4-2 Monocyte chemoattractant protein-1 (MCP-1/CCL2).........5
1.4-3 Reactive oxygen species (ROS)............5
1.4-4 E-1 (ET-1)..................6
1.4-5 Von Willebrand factor (vWF)..............6
1.4 Hypothesis...............7
Chapter 2 Materials and Methods............8
2.1 Complete-carotid-artery-ligation mouse model...........8
2.2 Histological analysis..............8
2.3 Immunofluorescence staining.............9
2.4 Dihydroethidium (DHE) staining............9
2.5 Ultrasound image...............9
2.6 Cell culture................10
2.7 Cell viability assay................10
2.8 Western blotting...............10
2.9 Statistical analysis...............11
Chapter 3 Results................12
3.1 Triterpenoids (GAs) prevented neointima formation-induced by complete carotid artery ligation in mice...............12
3.2 GAs inhibited disturbed flow-induced monocyte infiltration......13
3.3 GAs ameliorated reactive oxygen species (ROS) accumulation, apoptosis, and excessive regeneration induced by disturbed flow in the endothelium.......13
3.4 GAs inhibited monocytes recruitment under turbulence blood flow.....14
3.5 GAs reduced ROS accumulation in the endothelium after ligation.....15
3.6 GAs reduced the induction of endothelin-1 (ET-1) by ligation in the endothelium.15
3.7 GAs alleviated Von Willebrand factor (vWF) in endothelium.....15
3.8 GAs reduced ET-1 and VCAM-1 protein levels in ligated arteries.....16
3.9 GAs protected endothelial cells against H2O2-induced cell death in vitro....16
3.10 Delayed GAs treatment maintained its anti-atherogenic activities......17
Chapter 4 Discussion..............18
Chapter 5 Conclusion...............21
Chapter 6 Reference...............22
Chapter 7 Figure...............32
Figure 1. Complete carotid artery ligation-induced oscillatory blood flow and narrowed lumens.................32
Figure 2. Subcutaneous GAs prevented disturbed blood flow-induced neointima formation.................33
Figure 3. Oral GAs prevented disturbed blood flow-induced neointima formation...34
Figure 4. Monocyte infiltration was inhibited in GAs-treated mice.........35
Figure 5. GAs alleviated disturbed flow-induced oxidative stress in the endothelium..36
Figure 6. GAs protected endothelium from apoptosis induced by ligation in mice...37
Figure 7. Less proliferated endothelium was detected in GAs-treated mice....38
Figure 8. Structure of carotid arteries at early stage.........39
Figure 9. Monocyte Chemoattractant Protein-1 expression was downregulated in GAs-treated mice.................40
Figure 10. GAs alleviated disturbed flow-induced endothelial oxidative stress....41
Figure 11. GAs downregulated disturbed flow-induced endothelin-1 (ET-1) expression...42
Figure 12. Endothelial vWF induction by disturbed flow was inhibited by GAs....43
Figure 13. GAs treatment inhibited the induction of ET-1 and VCAM-1 proteins....44
Figure 14. GAs inhibited H2O2-induced cell death in HUVEC........45
Figure 15. Delayed GAs treatments retained the anti-atherogenic activities.....46
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