The role of reactive oxygen species in atherogenesis

描述（由申请人提供）：已提出在动脉壁中积累的氧化脂质和/或氧化脂蛋白在动脉粥样硬化形成中起关键作用。最近的研究数据表明，氧化脂质的致动脉粥样硬化作用至少部分与其在血管细胞中诱导活性氧（ROS）的能力有关。血管细胞中增加的ROS被认为诱导多种蛋白质的表达，这些蛋白质被认为参与炎性细胞对内皮的粘附、血管细胞的增殖和死亡。活性氧在动脉粥样硬化形成中起作用的理论很有吸引力，但尚未得到证实。本项目中描述的研究目标是使用转基因动物模型直接测试以下假设：ROS通过增加脂质过氧化和/或增加血管细胞对氧化脂质的敏感性在动脉粥样硬化形成中发挥作用。在这个项目中，我们将使用转基因小鼠模型，过表达人铜/锌超氧化物歧化酶（Cu/Zn-SOD），人过氧化氢酶或Cu/Zn-SOD和过氧化氢酶转基因。我们选择使用这些小鼠，因为超氧化物和过氧化氢被认为是在血管细胞介导的脂质氧化和氧化脂质诱导的致动脉粥样硬化活动中发挥作用的因素。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）敲除小鼠杂交。纯合子ApoE基因敲除小鼠在动脉壁中积累氧化脂质，并自发发展动脉粥样硬化病变，其形态特征与人类中发生的动脉粥样硬化病变非常相似。该项目包括三个具体目标：1）确定抗氧化酶的过度表达是否减少动脉粥样硬化的发展; 2）确定抗氧化酶的过度表达是否影响血管细胞对氧化脂质的反应; 3）确定抗氧化酶的过度表达是否减少脂质过氧化。如果上述假设是正确的，过表达Cu/Zn-SOD和/或过氧化氢酶的小鼠将显示出减少的动脉粥样硬化病变，这将与动脉壁中氧化脂质的积累减少和/或血管细胞对氧化脂质的反应降低相关。

DESCRIPTION (provided by applicant): Oxidized lipids and/or oxidized lipoproteins accumulated in the arterial wall have been proposed to play a critical role in atherogenesis. Data from recent studies suggest that the atherogenic action of oxidized lipids is, at least in part, associated with its ability to induce reactive oxygen species (ROS) in vascular cells. Increased ROS in vascular cells are believed to induce expression of a variety of proteins that are thought to be involved in adherence of inflammatory cells to the endothelium, proliferation and death of vascular cells. The theory that ROS play a role in atherogenesis is attractive, but is still unproven. The goal of the research described in this project is to use transgenic animal models to test directly the following hypothesis: ROS play a role in atherogenesis by increasing lipid peroxidation and/or increasing the sensitivity of vascular cells to oxidized lipids. In this project, we will use transgenic mouse models that overexpress human Cu/Zn superoxide dismutase (Cu/Zn-SOD), human catalase or both Cu/Zn-SOD and catalase transgenes. We have chosen to use these mice because superoxide and hydrogen peroxide are proposed to be factors that play a role in both vascular cell-mediated lipid oxidation and oxidized lipid-induced atherogenic activities. The transgenic mice overexpressing Cu/Zn-SOD and/or catalase will be crossbred into the apolipoprotein E (ApoE) knockout mice. The homozygous ApoE knockout mice accumulate oxidized lipids in the arterial wall and spontaneously develop atherosclerotic lesions with morphological features closely resembling the atherosclerotic lesions that occur in humans. This project consists of three specific aims: 1) to determine if overexpression of antioxidant enzymes reduces the development of atherosclerosis; 2) to determine if overexpression of antioxidant enzymes affects the response of vascular cells to oxidized lipids; and 3) to determine if overexpression of antioxidant enzymes reduces lipid peroxidation. If the hypothesis described above is correct, mice overexpressinq Cu/Zn-SOD and/or catalase will show reduced atherosclerotic lesions, which will correlate to a decreased accumulation of oxidized lipids in the arterial wall and/or a reduced response of vascular cells to oxidized lipids.