Effect of antioxidant enzymes on BaP-induced atherogenesis

抗氧化酶对 BaP 诱导的动脉粥样硬化的影响

• 批准号: 7211945
• 负责人: ZHONGMAO GUO
• 金额: $ 33.96万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-04 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211945
• 关键词: 3-nitrotyrosine; Adhesions; Animal Model; Animals; Antioxidants; Aorta; Apolipoprotein E; Apoptosis; Aromatic Polycyclic Hydrocarbons; Arterial Fatty Streak; Atherosclerosis; Benzo(a)pyrene; Blood Vessels; Carcinogens; Cell Proliferation; Cells; Coronary heart disease; Crossbreeding; Cuprozinc Superoxide Dismutase; DNA Damage; Development; Electrons; Endothelial Cells; Environmental Pollutants; Enzymes; Event; Exposure to; Flowers; Gene Expression; Generations; Human; Hydrogen Peroxide; Inflammatory; Injury; Laboratories; Lesion; Lipid Peroxidation; Lymphocyte; Malignant Neoplasms; Measures; Mus; Mutation; Numbers; Oxidation-Reduction; Process; Protein Overexpression; Proteins; Quinones; Reactive Oxygen Species; Relative (related person); Research; Role; Smooth Muscle Myocytes; Stroke; Superoxides; Testing; Transgenic Mice; Water; Yang; atherogenesis; benzoquinone; catalase; cell type; macrophage; monocyte; mouse model; oxidized lipid; response; size; theories; tool

DESCRIPTION (provided by applicant): Benzo[a]pyrene (BaP) is an environmental pollutant. Besides inducing cancers in humans, BaP has been shown to promote the development of atherosclerosis, which is the primary cause of coronary heart disease and stroke. The mechanism underlying the atherogenic action of BaP remains unknown. A currently popular theory postulates atherosclerosis as an inflammatory process driven by reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. BaP has been shown to increase intracellular ROS. Thus, the project described herein hypothesizes that generation of ROS in vascular cells is a key mechanism by which BaP promotes atherogenesis. Our laboratory has generated mouse models that overexpress Cu/Zn-superoxide dismutase (Cu/Zn-SOD) or catalase alone, or both Cu/Zn-SOD and catalase. Cu/Zn-SOD is a protein that converts superoxide to hydrogen peroxide, while catalase destroys hydrogen peroxide by converting it to water. As the relative contribution of different ROS to atherosclerosis might vary, our animal models provided a valuable tool for testing the role of superoxide and hydrogen peroxide in BaP-induced atherosclerosis. The transgenic mice overexpressing Cu/Zn-SOD and/or catalase have been crossbred into the apolipoprotein E (ApoE)-deficient mice, which spontaneously develop atherosclerotic lesions with morphological features closely resembling the atherosclerotic lesions that occur in humans. In this project, the ApoE-deficient mice, with or without overexpression of Cu/Zn-SOD and/or catalase, will be treated with BaP. We will determine: (1) whether overexpression of antioxidant enzymes inhibits BaP-induced atherogenesis and reduces the accumulation of inflammatory cells within the atherosclerotic lesions, (2) whether overexpression of antioxidant enzymes reduces BaP-induced accumulation of oxidized lipids and nitrotyrosine in the arterial wall, and (3) whether overexpression of antioxidant enzymes reduces BaP-induced atherogenic events in vascular cells, and inhibits BaP-induced gene expression and transcriptional factor activation. If our hypothesis described above is correct, BaP-induced atherosclerotic lesions will be smaller in mice overexpressing Cu/Zn-SOD and/or catalase, which will correlate to a decreased oxidative injury in the arterial wall and/or a reduced response of vascular cells to BaP.

说明(申请人提供)：苯并[a]芘(BaP)是一种环境污染物。除了诱发人类癌症外，BaP还被证明可以促进动脉粥样硬化的发展，而动脉粥样硬化是冠心病和中风的主要原因。BaP致动脉粥样硬化作用的机制尚不清楚。目前流行的一种理论假设动脉粥样硬化是由超氧化物和过氧化氢等活性氧物种(ROS)驱动的炎症过程。BaP被证明可以增加细胞内的ROS。因此，这里描述的项目假设在血管细胞中产生ROS是BaP促进动脉粥样硬化形成的关键机制。我们实验室已经建立了铜/锌-超氧化物歧化酶(铜/锌-超氧化物歧化酶)或单独表达过氧化氢酶或同时表达铜/锌-超氧化物歧化酶和过氧化氢酶的小鼠模型。铜/锌-超氧化物歧化酶是一种将超氧化物转化为过氧化氢的蛋白质，而过氧化氢酶通过将过氧化氢转化为水来破坏过氧化氢。由于不同的ROS对动脉粥样硬化的相对贡献可能不同，我们的动物模型为检测超氧化物和过氧化氢在BaP诱导的动脉粥样硬化中的作用提供了一个有价值的工具。高表达铜/锌-超氧化物歧化酶和/或过氧化氢酶的转基因小鼠被杂交成载脂蛋白E(ApoE)缺陷的小鼠，这些小鼠自发地形成与人类动脉粥样硬化病变相似的形态特征的动脉粥样硬化病变。在这个项目中，ApoE缺陷小鼠，无论是否有铜/锌-超氧化物歧化酶和/或过氧化氢酶过表达，都将被BaP治疗。我们将确定：(1)抗氧化酶的过表达是否抑制BaP诱导的动脉粥样硬化形成并减少炎症细胞在动脉粥样硬化病变中的积聚；(2)抗氧化酶的过表达是否减少BaP诱导的氧化脂质和硝基酪氨酸在动脉壁的积聚；(3)抗氧化酶的过表达是否减少BaP诱导的血管细胞内的动脉粥样硬化事件，并抑制BaP诱导的基因表达和转录因子激活。如果我们的假设是正确的，在过量表达铜/锌-超氧化物歧化酶和/或过氧化氢酶的小鼠中，BaP诱导的动脉粥样硬化病变将较小，这将与动脉壁氧化损伤减少和/或血管细胞对BaP的反应减少相关。