NITRIC OXIDE/SUPEROXIDE IN LIPID VASCULAR DISEASE

描述（改编自研究者摘要）：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， 众所周知的风险因素，其发展。 血管异常， 部分由于高胆固醇血症，存在于明显的 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（NO）和超氧阴离子在胆固醇诱导的血管扩张中的作用 功能障碍和动脉粥样硬化的关系尚不清楚。 NO生成于 内皮细胞的eNOS和可以灭活超氧阴离子。 超氧阴离子被SOD清除。 该项目旨在 确定NO和超氧化物在胆固醇诱导的血管扩张中的作用 过度表达eNOS，CuZnSOD和MnSOD基因的功能障碍， 高胆固醇血症的兔子 该项目旨在确定 内皮型一氧化氮合酶（eNOS）和超氧化物歧化酶的作用 (SOD)在胆固醇诱导的血管功能障碍中， 内皮eNOS、铜锌超氧化物歧化酶（CuZnSOD）和 锰超氧化物歧化酶（MnSOD）在高胆固醇血症家兔体内的作用 颈动脉 本研究的长期目标是研究 NO和超氧阴离子在动脉粥样硬化形成中的作用。 eNOS和SOD过表达 (both同种型）在兔动脉壁中的表达 使用腺病毒载体进行基因转移。 胆固醇性血管炎 将在用表达eNOS的载体治疗的动物中比较功能障碍 和/或SOD和对照。 这些研究的结果应该提供 关于NO和超氧阴离子在 胆固醇诱导的血管功能障碍，数据可能提供有用的 基因治疗为基础的战略发展的信息， 治疗这种疾病。 这项研究的长期目标是 探讨NO和SOD在动脉粥样硬化形成中的作用。 eNOS和SOD 动脉中的过表达将使用基因转移在体内进行 使用腺病毒载体的技术。 胆固醇性血管炎 将在用表达eNOS的载体治疗的动物中比较功能障碍 和/或SOD和对照。 具体目的1是确定eNOS在胆固醇诱导的 血管功能障碍 推测NOS活性和cGMP水平 减少动脉粥样硬化引起的血管功能障碍， eNOS活性和cGMP水平的恢复改善血管反应。 具体目标2是确定SOD是否是血管扩张的重要调节剂 语气 假设SOD的腺病毒载体减弱了 胆固醇诱导的血管功能障碍，CuMnSOD是最 两种SOD同工酶的活性。 具体目标3是确定eNOS和SOD在 胆固醇诱导的血管功能障碍。 它是假设 SOD与eNOS共表达可增强血管舒张。

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.