MOLECULAR MECHANISMS OF CHEMICAL ATHEROGENESIS

化学性动脉粥样硬化的分子机制

• 批准号: 6283570
• 负责人: Kenneth S. Ramos
• 金额: $ 13.25万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-09-03 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6283570
• 关键词: affinity chromatography; antioxidants; aromatic hydrocarbon receptor; atherosclerosis; benzopyrenes; binding proteins; complementary DNA; crosslink; environmental toxicology; gel mobility shift assay; gene expression; genetic promoter element; genetic regulation; genetic transcription; glutarates; immunoprecipitation; laboratory mouse; oncogenes; pathologic process; polymerase chain reaction; protein protein interaction; site directed mutagenesis; tissue /cell culture; vascular smooth muscle; western blottings

Environmental chemicals are significant risk factors for atherosclerotic vascular disease, but molecular mechanisms of atherogenesis have not been elucidated with certainty. Research in this laboratory during the previous funding cycle established that transcriptional deregulation of gene expression by aromatic hydrocarbons is a critical event in the induction of proliferative (i.e. atherogenic) phenotypes in vascular smooth muscle cells (vSMCs). Challenge with atherogenic hydrocarbons was shown to alter redox status and trigger a complex cellular response that culminates in modulation of vascular gene expression. Of particular relevance was the finding that functional interactions between aryl hydrocarbon receptor (AhR) and proteins that bind the antioxidant/electrophile response element (AREBpRE) are central to the loss of transcriptional control in hydrocarbon-treated cells. On the basis of these findings our unifying hypothesis is that deregulation of gene expression in vSMCs by aromatic hydrocarbons involves complex interactions between activated ARE/EpRE binding proteins, AhR, and co-regulators of transcription during the course of the atherogenic response. To test this hypothesis, experiments are proposed to purify and clone AREJEpRE binding proteins from vascular tissue following chemical injury, evaluate the role of HMG-1 (Y) as a co-regulator of ARFJEpRE-regulated gene transcription in vSMCs, and characterize promoter-specific patterns of trans-regulation in vSMCs. These studies will enable us to define the role of ARE/EpRE binding proteins in oxidant-induced atherogenesis and identify critical transacting factors involved in the atherogenic response to environmental injury.

环境化学物质是动脉粥样硬化性血管疾病的重要危险因素，但动脉粥样硬化形成的分子机制尚未明确阐明。该实验室在上一个资助周期中的研究表明，芳香烃对基因表达的转录失调是诱导血管平滑肌细胞（vSMC）增殖（即致动脉粥样硬化）表型的关键事件。研究表明，致动脉粥样硬化碳氢化合物的挑战会改变氧化还原状态并引发复杂的细胞反应，最终导致血管基因表达的调节。特别重要的是，芳基碳氢化合物受体 (AhR) 和结合抗氧化剂/亲电子反应元件 (AREBpRE) 的蛋白质之间的功能相互作用是碳氢化合物处理细胞中转录控制丧失的核心。基于这些发现，我们的统一假设是，芳香烃对 vSMC 中基因表达的失调涉及致动脉粥样硬化反应过程中激活的 ARE/EpRE 结合蛋白、AhR 和转录共调节因子之间的复杂相互作用。为了检验这一假设，提出了实验，从化学损伤后的血管组织中纯化和克隆 AREJEpRE 结合蛋白，评估 HMG-1 (Y) 作为 vSMC 中 ARFJEpRE 调节基因转录的共同调节因子的作用，并表征启动子- vSMC 中反式调节的特定模式。这些研究将使我们能够定义 ARE/EpRE 结合蛋白在氧化剂诱导的动脉粥样硬化形成中的作用，并确定参与对环境损伤的动脉粥样硬化反应的关键交易因子。