Vascular Toxicity of Aldehydes

醛的血管毒性

• 批准号: 6732080
• 负责人: Aruni Bhatnagar
• 金额: $ 37.3万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-03 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6732080
• 关键词: SDS polyacrylamide gel electrophoresis; acrolein; aldehydes; apolipoprotein E; atherosclerosis; autoantibody; biological signal transduction; blood lipoprotein metabolism; blood toxicology; cardiovascular disorder risk; cell adhesion molecules; environmental exposure; enzyme linked immunosorbent assay; genetically modified animals; high density lipoproteins; high performance liquid chromatography; hypercholesterolemia; immunocytochemistry; laboratory mouse; low density lipoprotein; low density lipoprotein receptor; mass spectrometry; phosphatidylcholine sterol acyltransferase; western blottings

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.

描述（由申请人提供）：大量流行病学数据表明，接触醛类或产生醛类的污染物会增加患心血管疾病的风险。然而，醛影响心血管健康的机制尚不清楚。我们认为，接触环境醛类如丙烯醛或反式2-己烯醛会加剧动脉硬化。根据我们的初步结果，我们认为醛暴露会导致脂蛋白修饰，从而诱发血管炎症，并失调细胞生长，从而导致更广泛、不稳定的细胞病变的形成。为了测试特定目标 1 中的这一假设，我们将研究暴露于吸入丙烯醛或膳食己烯醛或丙烯醛如何影响野生型、apoE 和低密度脂蛋白受体缺失小鼠的动脉粥样硬化进展。我们还将确定醛类的动脉粥样硬化性是否受高胆固醇血症程度的调节。该项目的第二个目标是阐明醛引起的脂蛋白变化。为此，我们将检查醛暴露小鼠中脂蛋白变化的严重性和程度，并测试醛暴露是否会导致脂蛋白的修饰、交联或聚集，并引发针对蛋白质-醛加合物的自身抗体的产生。我们的最终目标是描述醛诱导的脂蛋白修饰的动脉粥样硬化后果。我们将确定醛暴露引起的修饰是否会增加脂蛋白的致动脉粥样硬化性，以及醛是否通过阻止 HDL（高密度脂蛋白）颗粒的成熟来破坏胆固醇代谢。最后，我们将检查乙醛引起的血脂异常是否是由于卵磷脂：胆固醇酰基转移酶（LCAT）的抑制所致，以及 LCAT 缺陷小鼠中血脂异常的变化是否减少。该项目的结果将提供有关环境中毒性最强、含量最丰富的污染物对动脉硬化影响的新信息，并揭示它们增加心脏病风险的机制——心脏病是工业化世界的首要死因。这些研究的成功完成将构成未来人类风险和易感性评估的基础。