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: 7324794
• 负责人: ZHONGMAO GUO
• 金额: $ 32.23万
• 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/7324794
• 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

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.

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 显示可促进动脉粥样硬化的发展，动脉粥样硬化是冠心病的主要原因 和中风。 BaP 致动脉粥样硬化作用的机制仍不清楚。目前A 流行理论假设动脉粥样硬化是由活性氧驱动的炎症过程 （ROS），例如超氧化物和过氧化氢。 BaP 已被证明可以增加细胞内 ROS。 因此，本文描述的项目假设血管细胞中 ROS 的产生是一个关键机制 BaP 促进动脉粥样硬化形成。我们的实验室已经生成了过度表达的小鼠模型 Cu/Zn-超氧化物歧化酶 (Cu/Zn-SOD) 或单独的过氧化氢酶，或同时使用 Cu/Zn-SOD 和过氧化氢酶。铜/锌SOD 是一种将超氧化物转化为过氧化氢的蛋白质，而过氧化氢酶则通过以下方式破坏过氧化氢： 将其转化为水。由于不同活性氧对动脉粥样硬化的相对贡献可能有所不同，我们的动物 模型提供了一个有价值的工具来测试超氧化物和过氧化氢在 BaP 诱导中的作用 动脉粥样硬化。过表达 Cu/Zn-SOD 和/或过氧化氢酶的转基因小鼠已被杂交成 载脂蛋白 E (ApoE) 缺陷小鼠会自发发生动脉粥样硬化病变 形态特征与人类发生的动脉粥样硬化病变非常相似。在这个项目中， 具有或不具有 Cu/Zn-SOD 和/或过氧化氢酶过度表达的 ApoE 缺陷小鼠将接受 巴普。我们将确定：（1）抗氧化酶的过度表达是否会抑制 BaP 诱导的 动脉粥样硬化形成并减少动脉粥样硬化病变内炎症细胞的积累，(2) 抗氧化酶的过度表达是否会减少 BaP 诱导的氧化脂质积累以及 动脉壁中的硝基酪氨酸，以及（3）抗氧化酶的过度表达是否会降低 BaP- 诱导血管细胞中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。如果我们的上述假设是正确的，BaP 引起的动脉粥样硬化病变将是 在过度表达 Cu/Zn-SOD 和/或过氧化氢酶的小鼠中较小，这与氧化减少有关 动脉壁损伤和/或血管细胞对 BaP 的反应降低。