Oxidation Hypothesis--Paradoxes and Pitfalls

氧化假说引起了人们对它如何影响动脉粥样硬化形成过程的极大兴趣。尽管氧化应激有过多的促动脉粥样硬化作用，但有几个主要问题困扰着这一假说。这些包括，细胞对氧化应激的防御，运动的促氧化性质，多不饱和脂肪酸和雌激素，以及从血浆中快速清除氧化的低密度脂蛋白。有一个先验的需要修改假设，以包括这些因素。根据文献中的发现和我们的初步结果，我们提出：“血浆中的氧化应激可能导致组织(动脉)抗氧化酶的诱导升高，此外，这种氧化应激本身可能导致血浆胆固醇水平降低。”换句话说，氧化应激可能有助于维持组织中高水平的抗氧化保护，并结合血浆胆固醇的降低，将有助于减弱动脉粥样硬化的形成过程。我们提出了以下具体目标：1.证明氧化应激可导致组织抗氧化防御能力增强，从而减轻动脉粥样硬化。2.证明氧化应激可能通过促进氧化的脂蛋白的清除或通过胆固醇氧化产物介导的肝胆固醇合成减少而导致低密度脂蛋白水平的降低。3.证明在“有益的氧化应激习服阶段”补充抗氧化剂会产生反作用，减少血浆氧化应激的有益影响。4.探讨运动性氧化应激对低密度脂蛋白r-/-小鼠动脉粥样硬化病变消退的影响。由于脂肪条纹病变在生命早期就开始了，研究表明，从小摄入多不饱和脂肪酸丰富的饮食和运动将确保足够的抗氧化防御和对动脉粥样硬化的保护。运动也被推荐用于其他疾病，如糖尿病和高血压，这些疾病也与氧化应激有关。因此，这项研究的结果将具有深远的影响。

Oxidation hypothesis has generated an overwhelming interest in how it might affect the atherogenic process. Despite the plethora of pro-atherogenic effects of oxidative stress, several major problems plague the hypothesis. These include, cellular defense to oxidative stress, prooxidant nature of exercise, PUFA, and estrogens, and the rapid clearance of oxidized LDL from plasma. There is an a priori need to amend the hypothesis to include these factors. Based on findings in literature and our preliminary results, we propose that "oxidative stress in plasma might result in an elevated tissue (arterial) antioxidant enzyme induction and, in addition, such oxidative stress might itself could lead to lower plasma cholesterol levels." In other words, an oxidative stress might help to maintain a high level of antioxidant protection in tissues and combined with the lowering of plasma cholesterol, would help to attenuate the atherogenic process. We propose the following specific aims: 1. To demonstrate that oxidative stress would lead to elevated tissue antioxidant defense and decrease atherosclerosis. 2. To demonstrate that oxidative stress might lead to decreased LDL cholesterol levels via an enhanced clearance of oxidized lipoproteins or via decreased de novo liver cholesterol synthesis mediated by cholesterol oxidation products. 3. To demonstrate that antioxidant supplementation during the "beneficial oxidative stress acclimatization period" would be counter productive and reduce the beneficial effects of plasma oxidative stress. 4. To determine the effects of exercise-induced oxidative stress on the regression of atherosclerotic lesions in LDL r -/- mice. Since fatty streak lesion starts early in life, the study would suggest that the consumption of PUFA rich diet and exercise from childhood would ensure adequate antioxidant defense and protection from atherosclerosis. Exercise is also recommended for other diseases such as diabetes and hypertension, diseases in which oxidative stress is also implicated. Thus the outcome of this study will have far reaching implications.