Vascular Toxicity of Aldehydes

描述(由申请人提供)：广泛的流行病学数据表明，暴露在醛或醛产生的污染物中会增加心血管疾病的风险。然而，醛影响心血管健康的机制尚不清楚。我们认为，暴露于环境醛，如丙烯醛或反式-2-己烯醛，会加剧动脉硬化。根据我们的初步结果，我们认为醛暴露导致脂蛋白修饰，从而导致血管炎症，并调节细胞生长，从而导致更广泛的、不稳定的和细胞损伤的形成。为了在特定的目标1中验证这一假设，我们将检验吸入丙烯醛或饮食中的己烯醛或丙烯醛对野生型、载脂蛋白E和低密度脂蛋白受体缺失小鼠的动脉粥样硬化进展的影响。我们还将确定醛的动脉粥样硬化是否受高胆汁淤积症程度的调节。该项目的第二个目标是阐明乙醛诱导的脂蛋白变化。为此，我们将检查醛暴露小鼠脂蛋白变化的严重性和程度，并测试醛暴露是否会引起脂蛋白的修饰、交联或聚集，并引发针对蛋白醛加合物的自身抗体的产生。我们的最终目标是描绘乙醛诱导的脂蛋白修饰导致动脉粥样硬化的后果。我们将确定醛暴露引起的修饰是否增加了脂蛋白的动脉粥样硬化，以及醛是否通过阻止高密度脂蛋白(高密度脂蛋白)颗粒的成熟来扰乱胆固醇代谢。最后，我们将检查醛诱导的血脂异常是否由于卵磷脂：胆固醇酰基转移酶(LCAT)的抑制以及LCAT缺陷小鼠的血脂异常变化是否减轻。总而言之，该项目的结果将提供有关环境中最有毒和最丰富的污染物对动脉硬化的影响的新信息，并揭示它们导致心脏病风险的机制--心脏病是工业化世界的主要死亡原因。这些研究的成功完成将为今后评估人类风险和易感性奠定基础。

DESCRIPTION (provided by applicant): Extensive epidemiological data suggest that exposure to aldehydes or aldehyde-generating pollutants increases the risk of cardiovascular disease. However, the mechanisms by which aldehydes affect cardiovascular health are not known. We propose that exposure to environmental aldehydes such as acrolein or trans-2-hexenal exacerbates arteriosclerosis. Based on our preliminary results, we suggest that aldehyde exposure leads to lipoprotein modification, which induces vascular inflammation, and dysregulates cell growth, thereby resulting in the formation of more extensive, unstable, and cellular lesions. To test this hypothesis in Specific Aim 1 we will examine how exposure to inhaled acrolein or dietary hexenal or acrolein affects the progression of atherogenesis in wild type, apoE and low-density lipoprotein receptor- null mice. We will also determine whether the atherogenecity of aldehydes is modulated by the extent of hypercholestremia. The second aim of the project is to elucidate aldehyde-induced changes in lipoproteins. For this, we will examine the severity and the extent of lipoprotein changes in aldehyde-exposed mice and test whether aldehyde exposure causes modification, cross-linking or aggregation of lipoproteins and elicits the development of autoantibodies against protein-aldehyde adducts. Our final aim is to delineate the atherogenic consequences of aldehyde-induced lipoprotein modification. We will establish whether modifications due to aldehyde exposure increase the atherogenicity of lipoproteins, and whether aldehydes disrupt cholesterol metabolism by preventing the maturation of the HDL (high-density lipoprotein) particle. Finally, we will examine whether the aldehyde-induced dyslipidemia is due to the inhibition of lecithin: cholesterol acyl transferase (LCAT) and if the dyslipidemic changes are diminished in LCAT-deficient mice. Together the results of this project will provide new information about the effects of the most toxic and abundant pollutants in the environment on arteriosclerosis, and reveal mechanisms by which they contribute to the risk of heart disease - which is the leading cause of death in the industrialized world. Successful completion of these studies will form the basis of future assessment of human risk and susceptibility.