Role of aldehyde oxidation in atherosclerosis

描述（由申请人提供）：氧化低密度脂蛋白（Ox-LDL）被认为在动脉粥样硬化中起主要作用。尽管有大量的临床前证据表明其在动脉粥样硬化中的作用，但抗氧化剂的人体临床试验的负面结果是主要关注的问题。我们在本申请中解决了这一矛盾，并提出抗氧化剂会对脂质过氧化物衍生的醛转化为羧酸产生不利影响，并抑制可能抗动脉粥样硬化的产物的形成。基于初步数据，我们提出脂质过氧化衍生的甲醛氧化为二羧酸将通过促进钙化将脆弱的斑块转变为更稳定的斑块来保护。我们提出了三个具体的目标，将建立醛和进一步的氧化产物的形成，抗氧化剂在抑制抗动脉粥样硬化羧酸产物的形成的负面影响，并解决二羧酸的抗动脉粥样硬化作用的性质。总的来说，这项研究将提供一个机制为基础的解释抗氧化剂临床试验的失败，并将是唯一的，第一个我提出的“天然”抗炎产品（AZA）来自“有害的”脂质过氧化产物将作为抗动脉粥样硬化剂。这项研究总体上将为脂质过氧化和钙化之间的关系提供生物化学解释。这些研究的成功完成不仅有助于了解动脉粥样硬化发展的分子机制，而且有助于确定醛氧化作为促进和药物开发的分子靶点。

DESCRIPTION (provided by applicant): Oxidized low-density lipoprotein (Ox-LDL) has been suggested to play a major role in atherosclerosis. Despite the vast amount of pre-clinical evidence for its role in atherosclerosis, the negative outcomes of human clinical trials with antioxidants are of major concern. We address this paradox in this application and propose that antioxidants would adversely affect the conversion of lipid peroxide-derived aldehydes into carboxylic acids and inhibit the formation of products that could be anti-atherosclerotic. Based on preliminary data, we propose that the oxidation of lipid peroxidation-derived carboxaldehydes to dicarboxylic acids would be protective by shifting vulnerable plaques to more stable to plaque by promoting calcification. We propose three specific aims that would establish the formation of aldehyde and further oxidation products, the negative effects of antioxidants in inhibiting the formation of anti-atherosclerotic carboxylic acid products, and address the nature of anti-atherosclerotic effects of dicarboxylic acids. Overall, the study would provide a mechanism-based explanation for the failure of antioxidant clinical trials and will be unique and the first i proposing that a "natural" anti-inflammatory product (AZA) derived from "deleterious" lipid peroxidation products would act as an anti-atherosclerotic agent. The study overall will offer a biochemical explanation for the relationship between lipid peroxidation and calcification. The successful completion of the studies will not only help to understand the molecular mechanisms of atherosclerosis development but also would help to identify aldehyde oxidation as a molecular target for promotion and drug development.