Role of aldehyde oxidation in atherosclerosis

描述(申请人提供)：氧化型低密度脂蛋白(Ox-LDL)已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抗氧化剂在动脉粥样硬化中的作用，但抗氧化剂在人类临床试验中的负面结果令人担忧。我们解决了这一应用中的悖论，并提出抗氧化剂将对过氧化脂质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。根据初步数据，我们认为，通过促进钙化将脆弱的斑块转变为更稳定的斑块，脂质过氧化衍生的羧醛氧化为二元酸将具有保护作用。我们提出了三个具体目标，以确定醛和进一步氧化产物的形成，抗氧化剂在抑制抗动脉粥样硬化羧酸产物形成中的负面作用，以及解决二元酸抗动脉粥样硬化作用的性质。总体而言，这项研究将为抗氧化剂临床试验的失败提供一个基于机理的解释，并将是独一无二的，也是我第一次提出，从“有害的”脂质过氧化产物中提取的“天然”抗炎产品(AZA)将作为抗动脉粥样硬化剂。总体而言，这项研究将为脂质过氧化和钙化之间的关系提供一个生化解释。这些研究的成功完成不仅将有助于了解动脉粥样硬化发生的分子机制，而且将有助于确定乙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.