Effect of antioxidant enzymes on BaP-induced atherogenesis

苯并[a]芘(BaP)是一种环境污染物。除了在人体内诱发癌症外，苯并苯并不是一种 显示促进动脉粥样硬化的发展，而动脉粥样硬化是冠心病的主要原因 还有中风。BaP致动脉粥样硬化作用的机制尚不清楚。A目前 流行的理论假设动脉粥样硬化是由活性氧物种驱动的炎症过程 (ROS)，如超氧化物和过氧化氢。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ROS的产生是一个关键机制 BaP通过其促进动脉粥样硬化的形成。我们的实验室已经产生了过度表达的小鼠模型 铜/锌-超氧化物歧化酶或单独过氧化氢酶，或铜/锌-超氧化物歧化酶和过氧化氢酶。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 将其转化为水。由于不同的RO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诱导中的作用提供了有价值的工具。 动脉硬化。过表达铜/锌-超氧化物歧化酶和/或过氧化氢酶的转基因小鼠已经杂交到 载脂蛋白E(ApoE)缺陷小鼠，自发性地发生动脉粥样硬化病变 形态特征与人类动脉粥样硬化病变极为相似。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，将被治疗 巴普。我们将确定：(1)抗氧化酶的过度表达是否抑制了bap诱导的 动脉粥样硬化形成和减少炎症细胞在动脉粥样硬化病变内的积聚，(2) 抗氧化酶的过度表达是否减少了BaP诱导的氧化脂质和 动脉壁中的硝基酪氨酸，以及(3)抗氧化酶的过度表达是否降低BaP- 诱导血管细胞发生动脉粥样硬化事件，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，BaP诱导的动脉粥样硬化病变将是 小鼠过表达铜/锌-超氧化物歧化酶和/或过氧化氢酶的小鼠，这将与氧化减少相关 动脉壁损伤和/或血管细胞对BaP的反应减弱。

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.