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; 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血管疾病的重要危险因素，但是尚未确定动脉粥样硬化的分子机制。在先前的资金周期中，该实验室的研究表明，芳族碳氢化合物对基因表达的转录放松管制是在血管平滑肌细胞中诱导增殖（即动脉粥样硬化）表型（VSMC）中的增殖（即动脉粥样硬化）表型的关键事件。对动脉粥样硬化的碳氢化合物的挑战被证明会改变氧化还原状态，并触发复杂的细胞反应，最终导致调节血管基因表达。特别相关的是，发现芳基烃受体（AHR）与结合抗氧化剂/亲电反应元件（AREBPRE）之间的功能相互作用对于碳氢化合物处理细胞中转录控制的丧失至关重要。根据这些发现，我们统一的假设是，通过芳族烃对VSMC中的基因表达进行了管制，涉及激活的IS/Epre结合蛋白，AHR和转录的共同调节剂在动脉粥样硬化反应过程中的转录剂。为了检验这一假设，提出了实验来纯化和克隆在化学损伤后从血管组织中纯化的结合蛋白，评估HMG-1（Y）作为VSMC中ArfJepre调控基因转录的共同调节剂的作用，并在VSMC中表征启动子特异性模式。这些研究将使我们能够定义氧化剂诱导的动脉粥样硬化中的IS/EPRE结合蛋白的作用，并确定与环境损伤的动脉粥样硬化反应有关的关键交易因子。