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

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）： 老年血管细胞与年轻血管细胞相比，对促动脉粥样硬化因子的反应性更强。目前，血管细胞对致动脉粥样硬化刺激的敏感性随年龄增加的机制尚未完全了解。有迹象表明，活性氧（ROS），随着年龄的增长，作为细胞内的各种刺激的信使，诱导血管细胞中的动脉粥样硬化反应。在这个项目中，我们将使用转基因小鼠模型，过表达Cu/Zn-超氧化物歧化酶（SOD）或过氧化氢酶单独或过表达Cu/Zn-SOD和过氧化氢酶的组合来测试以下假设：ROS有助于内皮细胞（EC）对氧化脂质的敏感性与年龄相关的增加。我们选择测试EC对氧化脂质的敏感性，因为氧化脂质已被证明具有各种致动脉粥样硬化作用，例如，诱导EC死亡，增加白细胞与EC的粘附并减少内皮一氧化氮（NO）。我们选择使用过表达Cu/Zn-SOD和/或过氧化氢酶的小鼠，因为氧化脂质的致动脉粥样硬化作用至少部分与其诱导ROS的能力有关，例如，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。本课题的主要目的是：1）研究过表达Cu/Zn-SOD和/或过氧化氢酶是否能减轻内皮细胞NO代谢的增龄性变化; 2）研究过表达Cu/Zn-SOD和/或过氧化氢酶是否能减轻氧化脂质诱导的白细胞与内皮细胞粘附的增龄性增加; 3）研究Cu/Zn-SOD和/或过氧化氢酶的过表达是否减少内皮细胞中氧化脂质诱导的凋亡的年龄相关性增加。如果上述假设是正确的，减少细胞内的超氧化物和过氧化氢的过表达的Cu/Zn-SOD和/或过氧化氢酶将减弱年龄相关的增加的敏感性EC氧化脂质。这些信息对于理解ROS在动脉粥样硬化年龄相关发展中的作用是重要的，并可能导致动脉粥样硬化的潜在治疗策略。