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过程的极大兴趣。 尽管氧化应激的促动脉粥样硬化作用过多，但几个主要问题困扰着这一假说。 这些包括，细胞防御氧化应激，促氧化剂性质的运动，多不饱和脂肪酸，雌激素，和氧化低密度脂蛋白从血浆中的快速清除。 有一个先验需要修改的假设，包括这些因素。 基于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，并与降低血浆胆固醇相结合，将有助于减弱动脉粥样硬化过程。我们提出以下具体目标：1。证明氧化应激会导致组织抗氧化防御能力的提高和动脉粥样硬化的减少。 2.证明氧化应激可能通过增强氧化脂蛋白的清除或通过胆固醇氧化产物介导的肝脏胆固醇从头合成减少导致LDL胆固醇水平降低。 3.证明在“有益的氧化应激适应期”补充抗氧化剂会产生反作用，并降低血浆氧化应激的有益作用。 4.确定运动诱导的氧化应激对LDL 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，该研究表明，从儿童时期开始食用富含PUFA的饮食和运动将确保足够的抗氧化防御和保护免受动脉粥样硬化。 运动也被推荐用于其他疾病，如糖尿病和高血压，这些疾病也涉及氧化应激。 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.