運動訓練對氧化態低密度脂蛋白抑制
流體媒介之血管舒張作用的生理影響
摘要
前人的研究指出長期運動訓練可以促進內皮細胞型一氧化氮合成 (endothelial nitric oxide synthase, eNOS) 的基因表現，而流體誘發的血管舒張作用也被證明主要是透過eNOS基因表現的增加及活化。此外，氧化態低密度脂蛋白 (oxidized low density lipoprotein, Ox-LDL) 對eNOS基因表現有減少調節作用。為比較Ox-LDL對長期運動大鼠的流體誘發的動脈血管舒張能力的影響，本實驗特別設計了一套半活體灌流的裝置。週齡5週的大鼠施以分組後，運動組以原地跑步機進行每天60 min，每週5天，持續15-20週中等強度 (約70 % VO2peak) 的跑步運動訓練後，移除股動脈後施以不同流速 (0-15 ml/hr)、固定壓力 (60 mmHg) 的灌流程序。另外Ox-LDL對主動脈上eNOS蛋白質及mRNA的影響也分別以西方轉漬法 (Western blot) 及反轉錄聚合鏈鎖反應 (reverse transcriptional polymerase chain reaction, RT-PCR) 來分析。
結果發現：(1) Ox-LDL均會降低兩組大鼠流體誘發的動脈血管舒張能力；但是運動組在無論有無處理Ox-LDL條件之下，仍較控制組有較好的血管舒張能力；(2)運動組主動脈有較多的eNOS蛋白質及mRNA表現，雖然受Ox-LDL作用後，其eNOS蛋白質及mRNA的減少程度明顯高於控制組，但其eNOS蛋白質仍稍微多於未受Ox-LDL作用的控制組；(3) HDL可保護Ox-LDL對eNOS蛋白質的減少作用；(4) EGTA無法反轉Ox-LDL 對eNOS的抑制作用，表示抑制機制可能不是透過Ca+2活化的蛋白分解而引起；(5) 分離自運動組的LDL顯示較不易受到Cu+2在活體外 (in vitro) 所進行氧化作用的影響。
本實驗的結論為：長期運動訓練的大鼠較不易受到Ox-LDL造成的一些促粥狀動脈硬化 (proatherogenic) 效應的影響。然而，由於運動組eNOS蛋白質及mRNA表現明顯受到Ox-LDL的作用而減少，顯示在Ox-LDL存在條件下，愈多NO可能伴隨更多的危險。這個發現可能可以解釋少數優秀運動員，特別是優秀馬拉松選手，亦無法避免因粥狀動脈硬化性疾病導致的猝死案例。
關鍵詞：
內皮細胞型一氧化氮合成 (endothelial nitric oxide synthase, eNOS)
運動訓練 (exercise training)
氧化態低密度脂蛋白 (oxidized low-density lipoprotein, Ox-LDL)

Oxidized LDL and Flow-mediated Vasodilation
:Effect of Chronic Exercise Training
Abstract
Chronic exercise training has been shown to induce aortic endothelial nitric oxide synthase (eNOS) mRNA expression and activation resulting in a greater flow-induced vasodilation. On the other hand, oxidized low-density lipoprotein (Ox-LDL) has been shown to inhibit vasodilation by downregulating eNOS mRNA expression. To compare the effect of Ox-LDL on the flow-induced arterial vasodilatability in chronic exercise-trained and untrained rats, a semi in vivo perfusion system was designed. Five-week-old male Wistar rats were divided into exercise and control groups. After fifteen to twenty weeks of treadmill training at moderate intensity (approximately 70 % VO2peak) for 60 min per day, five days per week, femoral arteries were removed and perfused at varying flow rates under a constant pressure of 60 mmHg. The effects of Ox-LDL on aortic eNOS protein and mRNA expression were also examined by Western blot and reverse transcriptional polymerase chain reaction (RT-PCR).
The results showed that: (1) Ox-LDL reduced the flow-induced vasodilation in both groups; however, vessels from the exercise-primed rats exhibited better vasodilatability with and without Ox-LDL treatment; (2) eNOS protein and mRNA levels were elevated in the aortae of the exercise-primed rats. Exposure to Ox-LDL caused a prominent reduction of both eNOS mRNA and protein in the exercise-primed rats; however, the overall eNOS protein level in the aortae of the Ox-LDL treated exercise-primed rats was still slightly higher than that of the aortae of the control rats; (3) Cotreatment with HDL prevented Ox-LDL-induced aortic eNOS protein reduction in both groups; (4) EGTA treatment could not reverse the inhibitory effect, indicating that the mechanism may not by mediated by Ca+2-activated proteases; (5) LDL isolated from exercise-primed rats exhibited a higher resistance to Cu+2 induced oxidation in vitro.
In conclusion, the present study shows that chronic exercise-primed rats are less susceptible to some of the proatherogenic effects of Ox-LDL. However, in the exercise group, the eNOS protein and mRNA expression are more profundly inhibited by Ox-LDL, indicating that more risk will be accompanied by more NO if Ox-LDL is present. This finding may explain why atherosclerotic cardiac disease could develop in elite athletes, especially marathon runners, and has been a major cause of sudden death in athletes.
Key words:
eNOS: endothelial nitric oxide synthase
exercise training
Ox-LDL：oxidized low-density lipoprotein

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