動脈粥狀硬化是一種和慢性發炎相關的血管病變，在它發展的病程中，內皮細胞功能異常被認為是血管病變的開始。在動脈粥狀硬化發生的初期，會產生血管舒張反應降低和黏著分子表現量增加等的情形。之前的研究報告顯示，規律的運動可以降低動脈粥狀硬化的發生率，引起動脈粥狀硬化病程的逆行，甚至能夠增進冠狀動脈疾病病人血管內皮細胞的功能。我們和其他的研究者也指出，在正常或高血壓的動物，運動訓練能夠增加血管內由促效劑引起的一氧化氮的產生，以及增進內皮細胞引起的血管放鬆作用。由此得知，藉由運動訓練可以促進血管內皮細胞的功能，運動可以視為改善生活型態的方式之一。然而，運動如何對抗動脈粥狀硬化的保護作用，以及其背後的調控機轉仍不甚清楚。本研究目的，是去探討在不同的時間點，由高膽固醇引起的動脈粥狀硬化病程之血管變化情形，以及進一步探討運動訓練所引起的保護作用，我們將同時給予實驗動物高膽固醇飲食和運動訓練，分別在二、四、六、八週之後評估其血管功能的變化。我們的實驗設計，是將公的紐西蘭大白兔隨機分成四組，分別是：正常飲食控制組、高膽固醇飲食控制組、正常飲食訓練組和高膽固醇飲食訓練組。給予高膽固醇飲食組別的動物，是餵食含有百分之二高膽固醇的兔飼料，在二、四、六、八之週後引起其動脈粥狀硬化的發生;而給予運動訓練組別的動物，則是給予和高膽固醇飲食相同時程的運動訓練，在跑步機上以每小時0.88公里的速度，漸進地增加跑步時間，直至每天跑步三十至六十分鐘，每週跑步五天。在實驗結束後，取下牠們的胸主動脈做血管功能性和免疫組織化學的分析。結果發現：1) 高膽固醇飲食大於二週後，會產生血清中總膽固醇濃度和低密度脂蛋白濃度明顯增加的情形，而且在兔子胸主動脈，也發現由乙醯膽鹼誘導的血管舒張反應變差。而後者在二至六週的運動訓練介入後有顯著改善的現象; 2) 給予慢性運動八週後，發現在正常飲食的組別，運動訓練可明顯增進其胸主動脈由乙醯膽鹼誘導的血管舒張反應; 但是在高膽固醇飲食的組別，運動訓練只能部分回復其血管的功能; 3) 在胸主動脈，高膽固醇飲食及運動訓練對於影響乙醯膽鹼誘導血管舒張反應的作用，主要是由於改變血管內皮細胞衍生的一氧化氮及過極化因子的釋出; 4) 對胸主動脈而言，二至八週飲食和運動的介入，並不影響由SNP或A23187所誘導的血管舒張反應; 5) 高膽固醇飲食大於四週後，在胸主動脈發現有廣泛性脂肪堆積的情形，以及血管的黏著分子，如P-selectin、VCAM-1等，和MCP-1及iNOS的蛋白質表現量增加的情形; 而給予運動訓練可以有效抑制前述變化的產生。基於這些研究發現，我們得到的結論是：只要在血管未受到嚴重的傷害時，藉由運動訓練的介入，可以改善動脈粥狀硬化血管功能異常的情形。

Atherosclerosis is a cardiovascular disease associated with chronic inflammation. Endothelial dysfunction has been proposed to be the initial event during the progression of atherosclerosis. In the early stage of atherogenesis, the vasodilating response is impaired and the expression of adhesion molecules is upregulated. Previous studies have indicated that regular exercise reduces incidence of atherosclerosis, causes regression of atherosclerosis, and even corrects endothelial function in patients with coronary artery disease. We and other investigators have reported that exercise increases the agonist-stimulated NO release and enhances endothelium-dependent vasodilatation in vessels of normal or hypertensive animals. It is likely that exercise is one of the lifestyle modifications, which can improve endothelial function. However, the underlying mechanisms of the exercise-induced protective effect against atherosclerosis are still unknown. To study the time course in the progression of atherosclerotic vascular changes induced by hypercholesterolemia and the correcting effects of exercise training in rabbits, vascular function of thoracic aortas after 2, 4, 6, or 8 weeks of high cholesterol diet and/or exercise interventions was evaluated. Male New Zealand White rabbits were divided into 4 groups; i.e., normal diet control, high cholesterol diet control, normal diet with exercise, and high cholesterol diet with exercise. Animals in high cholesterol diet groups were fed 2% cholesterol rabbit chow for 2, 4, 6, or 8 weeks to induce atherosclerosis. Those in exercise groups ran on a treadmill at the speed of 0.88 km/h for up to 30-60 min/d, 5 d/wk for the same period of time as the diet intervention. Thoracic aortas were then isolated for functional and immunohistochemical analyses. We found that 1) high-cholesterol diet feeding for > 2 weeks increased serum concentrations of total cholesterol and LDL, and impaired acetylcholine (ACh)-evoked vasorelaxation in rabbit thoracic aortas. The latter could be reversed after 2-6 weeks of exercise intervention; 2) chronic exercise for 8 weeks significantly enhanced ACh-induced vasorelaxation in aortas of normal diet groups, whereas only partially reversed vascular function in aortas of high-cholesterol diet groups; 3) the effects of diet and exercise on ACh-evoked vasorelaxation in aortas were mainly due to alterations in the release of NO and endothelium-derived hyperpolarization factor; 4) sodium nitroprusside- or A23187-induced vasorelaxation in aortas was not affected after 2-8 weeks of diet and/or exercise interventions; 5) high-cholesterol diet feeding for > 4 weeks caused extensive lipid deposition and increased protein expression of P-selectin, VCAM-1, MCP-1 and iNOS in aortas, which could be largely reduced by chronic exercise. Based on these findings, we conclude that exercise intervention can ameliorate vascular dysfunction in atherosclerosis, as long as the vessels are not severely damaged.

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