NITRIC OXIDE/SUPEROXIDE IN LIPID VASCULAR DISEASE

一氧化氮/超氧化物在脂质血管疾病中的作用

• 批准号: 2503628
• 负责人: TIMOTHY O'BRIEN
• 金额: $ 10.02万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-05 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2503628
• 关键词: Adenoviridae; acetylcholine; anions; atherosclerosis; calcium flux; carotid artery; cyclic GMP; enzyme activity; gene expression; guanylate cyclase; hypercholesterolemia; ionophores; isozymes; laboratory rabbit; nitric oxide; nitric oxide synthase; superoxide dismutase; superoxides; transfection /expression vector; vascular endothelium; vasomotion

DESCRIPTION (Adapted from Investigator's Abstract): Atherosclerosis is a leading cause of death in the Western world, and hypercholesterolemia is a well-known risk factor for its development. Vasomotor abnormalities, in part due to hypercholesterolemia, are present prior to the onset of overt atherosclerosis and might play a role in disease progression. The role of nitric oxide (NO) and superoxide anion in cholesterol-induced vasomotor dysfunction and atherosclerosis is unclear. NO is generated in the endothelium by eNOS and can be inactivated with superoxide anions. Superoxide anions are scavenged by SOD. This project was designed to determine the role of NO and superoxide in cholesterol-induced vasomotor dysfunction by overexpressing the genes for eNOS, CuZnSOD and MnSOD in hypercholesterolemic rabbits. This project is designed to determine the role of endothelial nitric oxide synthase (eNOS) and superoxide dismutase (SOD) in cholesterol-induced vasomotor dysfunction by overexpressing the genes for endothelial eNOS, copper zinc superoxide dismutase (CuZnSOD)and manganese superoxide dismutase (MnSOD) in the hypercholesterolemic rabbit carotid artery. The long term goal of this research is to examine the role of NO and superoxide anion in atherogenesis. eNOS and SOD overexpression (both isoforms) in the arterial wall of rabbits will be achieved in vivo using gene transfer with adenoviral vectors. Cholesterol-induced vasomotor dysfunction will be compared in animals treated with vectors expressing eNOS and/or SOD and controls. Results from these studies should provide fundamental information about the roles of NO and superoxide anions in cholesterol-induced vasomotor dysfunction, and the data might provide useful information for the development of gene therapy-based strategies for the treatment of this disorder. The long-term goal of this research is to examine the role of NO and SOD in atherogenesis. eNOS and SOD overexpression in arteries will be done in vivo using a gene transfer technology that employs adenoviral vectors. Cholesterol-induced vasomotor dysfunction will be compared in animals treated with vectors expressing eNOS and/or SOD and controls. Specific Aim 1 is to determine the role of eNOS in cholesterol-induced vasomotor dysfunction. It is hypothesized that NOS activity and cGMP levels are reduced in atherosclerotic-induced vasomotor dysfunction and that restoration of eNOS activity and cGMP levels improves vasomotor responses. Specific Aim 2 is to determine if SOD is an important regulator of vasomotor tone. It is hypothesized that adenoviral vectors of SOD attenuate cholesterol-induced vasomotor dysfunction, and that CuMnSOD is the most active of the two SOD isoforms. Specific Aim 3 is to determine the relative roles of eNOS and SOD in cholesterol-induced vasomotor dysfunction. It is hypothesized that co-expression of SOD with eNOS will augment vascular relaxation.

描述(摘自研究人员摘要)：动脉粥样硬化是一种 在西方世界，高胆固醇血症是导致死亡的主要原因 影响其发展的众所周知的风险因素。血管运动异常，在 部分是由于高胆固醇血症，都是在临床发作之前就存在的 动脉粥样硬化，并可能在疾病进展中发挥作用。的作用 一氧化氮和超氧阴离子在胆固醇诱导的血管舒缩中的作用 功能障碍和动脉粥样硬化的关系尚不清楚。否是在 内皮型一氧化氮合酶激活内皮细胞，超氧阴离子可使其失活。 超氧阴离子被超氧化物歧化酶清除。这个项目的目的是 确定一氧化氮和超氧化物在胆固醇诱导的血管舒缩中的作用 内皮型一氧化氮合酶、铜锌超氧化物歧化酶和锰超氧化物歧化酶基因过表达所致的功能障碍 高胆固醇血症兔。该项目旨在确定 内皮型一氧化氮合酶和超氧化物歧化酶的作用 超氧化物歧化酶在胆固醇诱导的血管舒缩功能障碍中的作用 内皮eNOS、铜锌超氧化物歧化酶和铜锌超氧化物歧化酶基因 高胆固醇血症兔体内锰超氧化物歧化酶的变化 颈动脉。这项研究的长期目标是检验其作用 一氧化氮和超氧阴离子在动脉粥样硬化形成中的作用。ENOS与超氧化物歧化酶的过度表达 (这两种异构体)将在体内实现兔动脉壁中的 用腺病毒载体进行基因转移。胆固醇诱导的血管舒张剂 用表达eNOS的载体治疗的动物的功能障碍将进行比较 和/或超氧化物歧化酶和对照。这些研究的结果应该提供 关于NO和超氧阴离子在人体内的作用 胆固醇诱导的血管运动功能障碍，这些数据可能会提供有用的 关于开发基于基因治疗的策略的信息 治疗这种疾病的方法。这项研究的长期目标是 探讨一氧化氮和超氧化物歧化酶在动脉粥样硬化形成中的作用。ENOS与超氧化物歧化酶 在动脉中的过度表达将通过基因转移在体内完成 使用腺病毒载体的技术。胆固醇诱导的血管舒张剂 用表达eNOS的载体治疗的动物的功能障碍将进行比较 和/或超氧化物歧化酶和对照。 具体目的1是确定eNOS在胆固醇诱导中的作用 血管运动功能障碍。推测一氧化氮合酶活性和cGMP水平 在动脉粥样硬化引起的血管运动功能障碍中减少 ENOS活性和cGMP水平的恢复可改善血管舒缩反应。 具体目的2是确定超氧化物歧化酶是否是血管运动的重要调节因子 语气。据推测，携带超氧化物歧化酶的腺病毒载体可减弱 胆固醇引起的血管舒缩功能障碍，其中CuMnSOD是最 两种超氧化物歧化酶亚型的活性。 具体目标3是确定eNOS和SOD在脑出血中的相对作用 胆固醇引起的血管舒缩功能障碍。据推测， 联合表达超氧化物歧化酶和内皮型一氧化氮合酶可增强血管舒张性。