臺灣博碩士論文加值系統

動脈硬化的血管壁上有： (1)氧化低密度脂蛋白堆積 (2)白血球 (單核球和淋巴球)侵入 (3)平滑肌細胞表現型改變、增生及產生大量細胞外基質，由其發展過程中顯示動脈硬化可視為是一種發炎且與氧化壓力有關之疾病。促發炎媒介物-間白質 (interleukin-1, IL-1)與發炎 疾病有密切的關係，因此了解IL-1在動脈硬化進展時的表現及其功能是刻不容緩的；在氧化壓力方面，丹參內含強力抗氧化成分丹參酚酸B (Sal. B)，是一具有活血化瘀功能 的中藥。故本研究探討oxLDL對人類主動脈平滑肌細胞的細胞毒性、IL-1與IL-1ra之調控，以及Sal. B的處理是否會改變oxLDL對人類主動脈平滑肌細胞所造成的影響。實驗結果顯示含40及60 g/ml膽固醇的oxLDL，對誘導人類主動脈平滑肌細胞的活性下降具有時間與濃度關聯性，但是未氧化的LDL則無此效果。以40 g/ml oxLDL刺激細胞8小時，可增加細胞與annexin V的結合、染色質濃縮及凋亡-3 (caspase-3)的活化。OxLDL刺激人類主動脈平滑肌細胞IL-1與IL-1ra表現量會增加而且IL-1ra的出現較IL-1為晚，也會造成NF-B與AP-1活化。以1、2.5或10 g/ml Sal. B預處理細胞24小時，可減少oxLDL所引起的細胞毒性、細胞程式凋亡、凋亡-3活化及IL-1與IL-1ra的表現。由以上結果顯示富含抗氧化力的Sal. B可抑制動脈硬化進展，顯示Sal. B對動脈硬化的治療與預防將有很大的助益。

Atherosclerosis is the major contributor to the pathogenesis of myocardial and cerebral infarction. In the development of atherosclerotic lesions, three basic processes occur: (1) invasion of the artery wall by leukocytes, particularly monocytes and T-lymphocytes; (2) smooth muscle phenotypic modulation, proliferation, and synthesis of extracellular matrix; and (3) intracellular (macrophage and smooth muscle cells) lipoprotein uptake and lipid accumulation. The presence of inflammatory cells in the vascular wall suggests that atherosclerosis is an inflammatory and immune disease. Interleukin-1 (IL-1), an inflammatory mediator, has been implicated as a cytokine in the development and clinical sequelae of atherosclerosis. Fully understanding of the role of IL-1 and IL-1 receptor antagonist (IL-1ra) involved in the mechanism of atherosclerotic development is critically important. Oxidized low-density lipoprotein (oxLDL) is also involved in the development of atherosclerosis and antioxidants may protect component cells in the vessels against oxLDL-induced damages. Salvia miltiorrhiza (SM) is a herb widely used in the treatment of cardiovascular disorders and contains Salvianolic acid B (Sal. B), a potent antioxidant. In the present study, we examined the effects of Sal. B on the cytotoxicity and the expression of IL-1 and IL-1ra in oxLDL-treated human aortic smooth muscle cells (HASMCs). OxLDL (40 and 60 g cholesterol/ml) induced HASMCs death was time-and dose-dependent, whereas native LDL had no effect. HASMCs treated with 60 g/ml oxLDL for 8 hours increased annexin V binding, chromosome condensation and caspase-3 activation. OxLDL treatment also increase the expression of IL-1 and IL-1ra as well as the activation of NF-B and AP-1. Pretreatment of HASMCs with Sal. B (1 to 10 g/ml, 24 hours) attenuated the cytotoxicity, apoptosis, the expression of IL-1 and IL-1ra induced by oxLDL. These results demonstrate that Sal. B has anti-inflammatory and anti-atherosclerotic properties. The new mechanism of action of Sal. B, in addition to their previously reported inhibition of LDL oxidation, may help explain their efficacy in the treatment of atherosclerosis.

縮寫表………………………………………………………………… VII
中文摘要……………………………………………………………… 1.
英文摘要……………………………………………………………… 3.
壹、緒論……………………………………………………………… 5.
一、動脈硬化致病機轉……………………………………………… 6.
二、人類的低密度脂蛋白 (LDL)與氧化低密度脂蛋白 (oxLDL) 7.
三、平滑肌細胞在動脈硬化扮演之角色…………………………… 10.
四、間白質-1 (Interleukin-1)…………………………………… 16.
五、細胞死亡 (Cell death)……………………………………‥ 21.
六、應用於動脈硬化研究的動物模式……………………………… 22.
七、中、西醫學與動脈硬化………………………………………… 25.
八、研究動機………………………………………………………… 28.
貳、材料與方法……………………………………………………… 31.
一、儀器設備………………………………………………………… 32.
二、實驗材料與試劑………………………………………………… 33.
三、實驗用溶液配方………………………………………………… 36.
四、實驗方法………………………………………………………… 38.
1、人類低密度脂蛋白的純化與氧化……………………………… 38.
分離低密度脂蛋白
LDL的製備
LDL純化與氧化的檢測
LDL中膽固醇濃度之測定
2、實驗用Sal. B的純化與鑑定……………………………………… 42.
3、體外實驗…………………………………………………………… 43.
細胞培養 (Cell culture)
人類主動脈平滑肌細胞株免疫螢光染色法(Immunofluorescence staining)
細胞活性分析 (MTT assay)
酵素免疫法 (Enzyme-linked immunosorbent assay, ELISA)
西方點墨 (Western blotting) 分析法
共軛焦顯微鏡 (Confocal Microscope)
泡沫細胞 (Foam cell)之鑑定與統計
細胞程式凋亡 (Apoptosis)檢測與鑑定
凝膠遲滯分析 (Electrophoresis mobility shift assay, EMSA)
統計分析
4、動物實驗…………………………………………………………… 55.
動物飼養
動脈之擷取
組織之處理
組織之染色
參、實驗結果…………………………………………………………… 64.
肆、討論及結論………………………………………………………… 72.
附圖……………………………………………………………………… 80.
參考文獻……………………………………………………………… 100.
附件…………………………………………………………………… 121.

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