The Role of Oxidative Stress in Endothelial Aging

氧化应激在内皮衰老中的作用

• 批准号: 7204190
• 负责人: HONG YANG
• 金额: $ 15.96万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7204190
• 关键词: Adherence; Adhesions; Age; Age-Months; Aging; Animals; Antioxidants; Apoptosis; Area; Atherosclerosis; Attenuated; Biology of Aging; Blood Vessels; Cardiovascular Diseases; Carotene; Cell Aging; Cell Death; Cells; Chemicals; Cuprozinc Superoxide Dismutase; DNA; Development; Endothelial Cells; Enzymes; Excision; Generations; Goals; Human; Hydrogen Peroxide; Hypertension; Knowledge; Lead; Leukocytes; Lipids; Measures; Mediator of activation protein; Metabolism; Molecular Biology; Moon; Mus; Nitric Oxide; Oxidative Stress; Pathogenesis; Peroxonitrite; Probucol; Protein Overexpression; Proteins; Reactive Oxygen Species; Research; Role; Second Messenger Systems; Signal Transduction; Stimulus; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Therapeutic Studies; Tissues; Transgenic Mice; Transgenic Organisms; Vitamin E; Water; Wild Type Mouse; age related; aged; atherogenesis; cardiovascular disorder therapy; catalase; cell age; glutathione peroxidase; lipid I; macromolecule; mouse model; oxidized lipid; oxidized low density lipoprotein; response; second messenger; Adherence; Adhesions; Age; Age-Months; Aging; Animals; Antioxidants; Apoptosis; Area; Atherosclerosis; Attenuated; Biology of Aging; Blood Vessels; Cardiovascular Diseases; Carotene; Cell Aging; Cell Death; Cells; Chemicals; Cuprozinc Superoxide Dismutase; DNA; Development; Endothelial Cells; Enzymes; Excision; Generations; Goals; Human; Hydrogen Peroxide; Hypertension; Knowledge; Lead; Leukocytes; Lipids; Measures; Mediator of activation protein; Metabolism; Molecular Biology; Moon; Mus; Nitric Oxide; Oxidative Stress; Pathogenesis; Peroxonitrite; Probucol; Protein Overexpression; Proteins; Reactive Oxygen Species; Research; Role; Second Messenger Systems; Signal Transduction; Stimulus; Superoxide Dismutase; Superoxides; Testing; Therapeutic; Therapeutic Studies; Tissues; Transgenic Mice; Transgenic Organisms; Vitamin E; Water; Wild Type Mouse; age related; aged; atherogenesis; cardiovascular disorder therapy; catalase; cell age; glutathione peroxidase; lipid I; macromolecule; mouse model; oxidized lipid; oxidized low density lipoprotein; response; second messenger

DESCRIPTION (provided by applicant): Aged vascular cells show greater reactivity to pro-atherogenic factors as compared to their young counterparts. Currently, the mechanism responsible for the age-related increase in the sensitivity of vascular cells to atherogenic stimuli has not been fully understood. There are indicators that reactive oxygen species (ROS), which increase with age, function as intracellular messengers of various stimuli to induce atherogenic responses in vascular cells. In this project, we will use transgenic mouse models that overexpress Cu/Zn-superoxide dismutase (SOD) or catalase alone or overexpress Cu/Zn-SOD and catalase in combination to test the following hypothesis: ROS contribute to the age-related increase in the sensitivity of endothelial cells (ECs) to oxidized lipids. We have chosen to test the sensitivity of ECs to oxidized lipids because oxidized lipids have been shown to have various atherogenic actions, e.g., inducing EC death, increasing leukocyte adhesion to ECs and reducing endothelial nitric oxide (NO). We have chosen to use mice overexpressing Cu/Zn-SOD and/or catalase because the atherogenic action of oxidized lipids is, at least in part, associated with its ability to induce ROS, e.g., superoxide and hydrogen peroxide, in ECs. Cu/Zn-SOD is a major enzyme to convert intracellular superoxide to hydrogen peroxide, while catalase destroys hydrogen peroxide by converting it to water. This project contains three specific aims: 1) to study if overexpression of Cu/Zn-SOD and/or catalase attenuates age-related changes in endothelial NO metabolism; 2) to study if overexpression of Cu/Zn-SOD and/or catalase reduces age-related increase in oxidized lipid-induced adherence of leukocytes to ECs; 3) to study if overexpression of Cu/Zn-SOD and/or catalase reduces age-related increase in oxidized lipid-induced apoptosis in ECs. If the hypothesis described above is correct, reduction in intracellular superoxide and hydrogen peroxide by overexpression of Cu/Zn-SOD and/or catalase will attenuate the age-related increase in the sensitivity of ECs to oxidized lipids. Such information is important for understanding the role of ROS in the age-related development of atherosclerosis and could lead to potential strategies of therapy for atherosclerosis.

描述（由申请人提供）： 与年轻的同龄人相比，老化的血管细胞对促动脉粥样硬化因素的反应性更高。目前，尚未完全了解导致血管细胞对动脉粥样硬化刺激的敏感性增加的机制。有指标表明，随着年龄的增长，活性氧（ROS）充当各种刺激的细胞内信使，以诱导血管细胞中的动脉粥样硬化反应。在这个项目中，我们将使用过表达Cu/Zn-塞氧化剂歧化酶（SOD）或过氧化氢酶或过表达的转基因小鼠模型或过表达CU/Zn-SOD和CETALASE组合来测试以下假设：ROS有助于年龄相关的内皮细胞（ECS）对氧化脂质的敏感性的增加。我们选择测试EC对氧化脂质的敏感性，因为已证明氧化的脂质具有各种动脉粥样硬化作用，例如诱导EC死亡，对ECS的白细胞粘附增加并减少内皮氮氧化物（NO）。我们选择使用过表达Cu/Zn-SOD和/或过氧化氢酶的小鼠，因为氧化脂质的动脉粥样硬化作用至少部分与诱导ROS的能力相关，例如EC中的超氧化物和过氧化氢。 Cu/Zn-SOD是将细胞内超氧化物转化为过氧化氢的主要酶，而过氧化氢酶通过将其转化为水来破坏过氧化氢。该项目包含三个具体目标：1）研究Cu/Zn-SOD和/或过氧化氢酶的过度表达是否会减弱内皮无代谢的年龄相关的变化； 2）研究Cu/Zn-SOD和/或过氧化氢酶的过表达是否会减少与年龄相关的氧化脂质诱导的白细胞粘附于ECS的增加； 3）研究Cu/Zn-SOD和/或过氧化氢酶的过表达是否会减少EC中氧化脂质诱导的凋亡的年龄相关的增加。如果上述假设是正确的，则通过过表达Cu/Zn-SOD和/或过氧化氢酶的过表达减少细胞内超氧化物和过氧化氢，将减少ECS对氧化脂质的敏感性与年龄相关的增加。此类信息对于理解ROS在与年龄相关的动脉粥样硬化发展中的作用很重要，并可能导致潜在的动脉粥样硬化策略。