粥狀動脈硬化病理生成的起始過程中，受到化學梯度的趨化素吸引的單核球細胞藉由內皮黏附因子黏附上受損的血管壁，移行進入血管內皮細胞下層，高血糖或發炎因子的刺激促使內皮細胞損傷而造成血管內皮與單核球細胞的黏附增加，內皮黏附因子在這過程中扮演重要角色。抗氧化物具有抑制黏附因子表現，進而降低動脈硬化生成的作用。在本論文中研究銀杏萃取物對於高葡萄糖或細胞激素-腫瘤壞死因子刺激人類動脈內皮細胞黏附因子的影響，探討是否存有抗氧化之外的作用。
臨床研究顯示在糖尿病相關的動脈硬化上高血糖是一個獨立的危險因子。內皮細胞受到高葡萄糖(25 mM)刺激四天時會促使黏附因子表現增加，進而造成單核球細胞與內皮細胞的黏附。在高葡萄糖藉由滲透壓的刺激條件下，內皮細胞氧化壓力上升、細胞激素-IL-6分泌增加、轉錄因子STAT1/3活化，進而增加ICAM-1表現。銀杏萃取物可以減緩高葡萄糖刺激而增加的ICAM-1表現與單核球細胞與內皮細胞的黏附；抗氧化物NAC有類似銀杏萃取物減緩內皮細胞與單核球細胞黏附的效果。所以推測銀杏萃取物可能是透過降低高葡萄糖刺激增加的氧化壓力，進而減緩細胞內黏附因子表現。
銀杏萃取物可以減緩在TNF-α (2 ng/mL)刺激單核球細胞與內皮細胞的黏附，同時給于第一型血紅素氧化脢(HO-1)活性抑制劑：ZnPP IX或是SnPP IX時，銀杏萃取物減緩內皮與單核球細胞沾黏能力就喪失了，這結果推論第一型血紅素氧化脢在銀杏萃取物對抗TNF-α所促使單核球細胞沾黏能力扮演重要的角色。銀杏萃取物透過活化轉錄因子Nrf-2從細胞質移入細胞核，進而結合上第一型血紅素氧化酶基因的ARE (antioxidant response element) 活化位置，促使第一型血紅素氧化酶蛋白質生成增加，訊息傳遞機制推測可能是透過p38/Nrf-2路徑，而氧化壓力可能並無直接參與。所以銀杏萃取物透過選擇性的路徑增加第一型血紅素氧化酶生成而達到抗血管發炎。在動物實驗結果顯示，銀杏萃取物可以減緩股動脈損傷所造成單核球細胞黏附血管壁，同時可以增加損傷後的血管組織與單核球細胞第一型血紅素氧化酶生成。
根據實驗的結果推論，銀杏萃取物在保護內皮細胞在長時間處理高葡萄糖時，減緩單核球細胞沾黏的效果與減少氧化壓力有關。而在處理TNF-α時，銀杏萃取物對抗血管發炎的效果透過增加第一型血紅素氧化酶。因此提出一個新的機制在銀杏萃取物對抗粥狀動脈硬化生成與其他發炎反應。

An important initial event in the pathogenesis of atherosclerosis is adhesion of monocytes to arterial endothelial cells, followed by their transmigration into the sub-endothelial space along a chemotactic gradient. Endothelial adhesion molecules take part in this event and play important roles in atherogenesis. Hyperglycemia or proinflammatory cytokines have been proposed to trigger endothelial oxidative stress, facilitate monocyte adhesion to endothelial cells. Suppression of endothelial adhesion molecules by antioxidant agents have attenuated the processes leading to atherogenesis. In this study, ginkgo biloba extract (GBE) was used to suppress the high glucose- or TNF-α-induced expression of adhesion molecules in HAECs. The effect of GBE-induced HO-1 (heme oxygenase-1) on anti-atherogenesis was also investigated.
Clinical evidence suggests that hyperglycemia is an independent risk factor of diabetes-associated atherosclerosis. Exposure to high glucose (25mM) for 4 days induced expression of ICAM-1, enhancing monocyte adhesion to HAECs. High glucose treatment for 3 days, followed by treatment with GBE for 1 day, reduced high glucose-induced ROS generation, IL-6 secretion, IL-6-medilated activation of signal transducer and activator of transcription 1/3 (STAT1/3), and ICAM-1 accumulation in HAECs. NAC, an antioxidant agent, had a similar effect on suppressing high glucose-activated IL-6 secretion, ICAM-1 accumulation, and endothelial adhesiveness. These findings support the notion that GBE may use an antioxidant mechanism to inhibit intracellular redox-sensitive transcription pathways.
Pretreatment with GBE for 12 hours reduced TNF-α-stimulated endothelial adhesion, which could be attenuated by HO-1 inhibitors ZnPP IX or SnPP IX. These results suggest HO-1 plays a crucial role in GBE induced suppression of TNF-α-mediated monocyte adhesion. Furthermore, GBE induced expression of HO-1 by activating the translocation of transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2), and increasing its binding to the antioxidant response element (ARE) of the HO-1 promoter gene. In vivo study also showed that GBE treatment could reduce leukocyte adherence to injured arteries, and enhance HO-1 expression in circulating monocytes as well as in arteries after wire injury. These findings suggest that GBE could inhibit cytokine-induced endothelial adhesion by inducing HO-1 expression via activation of p38 and Nrf-2 pathways, a mechanism in which oxidative stress is not directly involved. GBE might exert its anti-atherogenesis and vascular protective effects by inducing vascular HO-1 expression.
These results suggest that the anti-atherogenic effect of GBE against HAECs under chronic exposure to high glucose is through antioxidant-dependent mechanism. The GBE augmented anti-atherogenic effect also involves inhibition of ROS-sensitive transcriptional pathways in high glucose-stimulated HAECs. Furthermore, in TNF-α-stimulated HAECs, GBE promotes anti-atherogenesis by directly inducing HO-1 transcriptional pathways.

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Acknowledgement
Contents 2
中文摘要 3
English abstract 5
List of abbreviations 8
Introduction 10
Hypothesis and aim of study 21
Materials and methods 26
Results 38
Discussions 57
Conclusion 70
References 72
Figures 83
Publications 106

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