在動脈硬化的形成過程當中，最先開始同時也是最重要的步驟為內皮細胞的功能不足。之前的研究顯示，動脈硬化的血管其內皮細胞的一氧化氮產量及血管舒張反應皆有變差的情形。已知內皮細胞一氧化氮合成酵素的活化是受到鈣離子所調控的，因此內皮細胞內的鈣離子濃度對於調節血管張力應該扮演一個重要的角色。已知運動能夠透過改善一些危險因子或內皮細胞功能來達到減緩動脈硬化的生成或減少其發生率。我們之前的研究也發現經過八週的運動訓練確實能夠增進在高血脂大白兔股動脈中由乙醯膽鹼所誘發的內皮細胞的鈣離子濃度增加及血管舒張反應。但是對於給予較短或不同時程的運動訓練對動脈硬化下內皮細胞鈣離子訊號及血管反應的影響則還不清楚。因此，我們將紐西蘭大白兔分為四組，分別為:正常飼料餵食控制組(NC)、正常飼料餵食運動組(NT)、高膽固醇飼料餵食控制組(HC)、與高膽固醇飼料餵食運動組(HT)。分別經過兩週、四週及六週的餵食及運動訓練後，取下股動脈做為實驗材料，以fura 2染色後將血管剪開並固定於平行流體室中，以螢光顯微鏡來觀察血管舒張反應及偵測內皮細胞內鈣離子訊號。我們的結果顯示1) 以苯甲麻黃素先收縮之股動脈經乙醯膽鹼誘發的血管舒張及內皮細胞內鈣離子上升反應在高膽固醇餵食四週及六週後明顯降低，但是運動訓練則改善了這樣的情況; 2) 先給予一氧化氮抑制劑L-NNA前處理，血管的舒張反應明顯下降，同時也使得餵食或運動的效果消失; 3) SNP或A23187所引發的血管舒張反應同樣的也因為高膽固醇餵食(>4wk)而有所下降，顯示血管可能因為高膽固醇餵食而產生了結構上的改變，同樣的，這些反應也能夠透過運動訓練而有所改善; 4) oil red O染色的結果則顯示隨著高膽固醇餵食越久，脂肪在血管壁的堆積情形越嚴重，而六週的運動訓練則明顯降低了脂肪的堆積; 5) 免疫染色的結果則發現高膽固醇餵食六週後的血管其iNOS及P-selectin皆會在動脈硬化斑處有所表現。由我們的實驗結果可部分解釋運動可減緩動脈硬化進行的機制。

In atherosclerosis, the initial and the most important event is endothelial dysfunction. Previous studies have shown that endothelial NO production and vascular endothelium-dependent relaxation are impaired during the process of atherosclerosis. It is known that the activation of endothelial NO synthase (eNOS) is Ca2+-dependent. Therefore, the endothelial intracellular calcium concentration (EC[Ca2+]i) is important in the regulation of vascular tone. Exercise can reduce the incidence and retard the progression of atherosclerosis by modifying some risk factors and increasing endothelial function. Our previous study has shown that 8 weeks of exercise enhances acetylcholine (ACh)-induced EC[Ca2+]i elevation and vasodilation in hypercholesterolemia. Whether parallel exercise training for various time periods affects EC[Ca2+]i signaling and vascular responses in atherosclerosis is unknown. To answer this question, male New Zealand White rabbits were divided into 4 groups: the normal diet control group (NC), the normal diet with exercise group (NT), the high-cholesterol diet control group (HC), and the high-cholesterol diet with exercise group (HT). Following 2, 4 or 6 weeks of the diet and/or exercise interventions, the rabbits were sacrificed, and femoral arteries were excised. En face preparations of the fura 2-loaded femoral arteries were mounted onto a flow chamber. Vasodilating responses and EC[Ca2+]i responses to agonists were determined under a fluorescent microscope. Our results showed that 1) high cholesterol diet feeding decreased ACh-induced vasodilation and EC[Ca2+]i elevation in phenylephrine-precontracted femoral arteries, but exercise reversed these responses in 4- and 6-week groups; 2) the pretreatment of L-NNA markedly decreased the ACh-induced vasodilation and EC[Ca2+]i elevation, and blunted diet/exercise effects; 3) results from SNP- or A23187-induced vasodilation implied that there might be some vascular structural changes during atherosclerosis progression; 4) results of oil red O staining demonstrated that there were fat deposits in HC and HT at all three time points, and exercise decreased fat deposits only in the 6-week group; 5) immunostaining results showed that high cholesterol diet feeding increased iNOS and P-selectin expression only at plaque areas in the 6-wk group. Our findings may partially explain the mechanisms of chronic exercise to retard the progression of atheroslcerosis.

英文摘要 ------------------------------------ 1
中文摘要 ------------------------------------ 2
圖目錄 ------------------------------------ 3
表目錄 ------------------------------------ 4
附圖目錄 ------------------------------------ 5
緒論 ------------------------------------ 6
材料 ------------------------------------ 11
方法 ------------------------------------ 16
結果 ------------------------------------ 25
討論 ------------------------------------ 30
結論 ------------------------------------ 38
圖 ------------------------------------ 39
表 ------------------------------------ 51
附圖 ------------------------------------ 53
參考文獻 ------------------------------------ 56

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