Effect of antioxidant enzymes on BaP-induced atherogenesis

描述（由申请人提供）：苯并[a]芘（BaP）是一种环境污染物。除了在人类中诱发癌症外，BaP已被证明可以促进动脉粥样硬化的发展，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认为动脉粥样硬化是由活性氧（ROS）（如超氧化物和过氧化氢）驱动的炎症过程。BaP已被证明可增加细胞内ROS。因此，本文描述的项目假设血管细胞中ROS的产生是BaP促进动脉粥样硬化形成的关键机制。我们的实验室已经建立了过表达Cu/ zn -超氧化物歧化酶（Cu/Zn-SOD）或过氧化氢酶单独或Cu/Zn-SOD和过氧化氢酶的小鼠模型。Cu/Zn-SOD是一种将超氧化物转化为过氧化氢的蛋白质，而过氧化氢酶通过将过氧化氢转化为水来破坏过氧化氢。由于不同ROS对动脉粥样硬化的相对贡献可能不同，我们的动物模型为测试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有价值的工具。将过表达Cu/Zn-SOD和/或过氧化氢酶的转基因小鼠与载脂蛋白E （ApoE）缺陷小鼠杂交，使其自发形成动脉粥样硬化病变，其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，apoe缺陷小鼠，无论是否过度表达Cu/Zn-SOD和/或过氧化氢酶，都将被BaP处理。我们将确定：(1)抗氧化酶的过表达是否能抑制bap诱导的动脉粥样硬化，减少动脉粥样硬化病变内炎症细胞的积累；(2)抗氧化酶的过表达是否能减少bap诱导的动脉壁氧化脂质和硝基酪氨酸的积累；(3)抗氧化酶的过表达是否能减少bap诱导的血管细胞粥样硬化事件。抑制bap诱导的基因表达和转录因子激活。如果我们上述的假设是正确的，那么在过度表达Cu/Zn-SOD和/或过氧化氢酶的小鼠中，BaP诱导的动脉粥样硬化病变会更小，这将与动脉壁氧化损伤减少和/或血管细胞对BaP的反应减少有关。

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.