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: 7744697
• 负责人: ZHONGMAO GUO
• 金额: $ 31.94万
• 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 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744697
• 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; Oxidation-Reduction; Process; Proteins; Quinones; Reactive Oxygen Species; Relative (related person); Research; Role; Smooth Muscle Myocytes; Stroke; Superoxides; Testing; Transgenic Mice; Water; Yang; atherogenesis; catalase; cell type; macrophage; monocyte; mouse model; overexpression; oxidized lipid; response; 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，苯并（a）芘还 显示促进动脉粥样硬化的发展，这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尚不清楚。当前 流行的理论假定动脉粥样硬化是由活性氧驱动的炎症过程 (ROS)如超氧化物和过氧化氢。BaP已显示增加细胞内ROS。 因此，本文所述的项目假设血管细胞中ROS的产生是关键机制 BaP通过其促进动脉粥样硬化形成。我们的实验室已经建立了小鼠模型， Cu/Zn-超氧化物歧化酶（Cu/Zn-SOD）或单独的过氧化氢酶，或Cu/Zn-SOD和过氧化氢酶两者。Cu/Zn-sod 是一种将超氧化物转化为过氧化氢的蛋白质，而过氧化氢酶则通过 转化为水由于不同ROS对动脉粥样硬化的相对贡献可能不同，我们的动物 模型提供了一个有价值的工具，用于测试超氧化物和过氧化氢在BaP诱导的 动脉粥样硬化将过表达Cu/Zn-SOD和/或过氧化氢酶的转基因小鼠杂交， 载脂蛋白E（ApoE）缺陷小鼠，自发发展动脉粥样硬化病变， 形态学特征非常类似于发生在人类中的动脉粥样硬化病变。在这个项目中， ApoE缺陷小鼠，有或没有Cu/Zn-SOD和/或过氧化氢酶的过表达，将用 BaP。我们将确定：（1）抗氧化酶的过度表达是否抑制了BaP诱导的细胞凋亡。 减少动脉粥样硬化病变内炎性细胞的积聚，（2） 抗氧化酶的过度表达是否减少了BaP诱导的氧化脂质的积累， 硝基酪氨酸在动脉壁，和（3）是否过表达的抗氧化酶减少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 因子激活如果我们上述的假设是正确的，那么BaP诱导的动脉粥样硬化病变将是 在过表达Cu/Zn-SOD和/或过氧化氢酶的小鼠中较小，这将与降低的氧化应激相关。 动脉壁损伤和/或血管细胞对BaP的反应减弱。

项目成果

Apolipoprotein E4 is deficient in inducing macrophage ABCA1 expression and stimulating the Sp1 signaling pathway.

• DOI: 10.1371/journal.pone.0044430
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Okoro EU;Zhao Y;Guo Z;Zhou L;Lin X;Yang H
• 通讯作者: Yang H

Nrf2-dependent induction of NQO1 in mouse aortic endothelial cells overexpressing catalase.

• DOI: 10.1016/j.freeradbiomed.2011.04.020
• 发表时间: 2011-07-01
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Lin, Xinghua;Yang, Hong;Zhou, LiChun;Guo, ZhongMao
• 通讯作者: Guo, ZhongMao

Cholecystokinin elevates mouse plasma lipids.

• DOI: 10.1371/journal.pone.0051011
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Zhou L;Yang H;Lin X;Okoro EU;Guo Z
• 通讯作者: Guo Z

Regulation of the Activity and Expression of Aryl Hydrocarbon Receptor by Ethanol in Mouse Hepatic Stellate Cells.

乙醇对小鼠肝星状细胞芳基烃受体活性和表达的调节。

• DOI: 10.1111/j.1530-0277.2012.01787.x
• 发表时间: 2012
• 期刊: Alcoholism, clinical and experimental research
• 作者: Zhang,HongFeng;Lin,XingHua;Yang,Hong;Zhou,LiChun;Guo,YangLin;Barnett,JoeyV;Guo,ZhongMao
• 通讯作者: Guo,ZhongMao