HYPERTENSION AND VASCULAR SUPEROXIDE GENERATION

高血压和血管超氧化物生成

• 批准号: 2668758
• 负责人: Patrick J Pagano
• 金额: $ 10.85万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2000-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668758
• 关键词: HYPERTENSION; VASCULAR; SUPEROXIDE; GENERATION

DESCRIPTION: (Adapted from abstract) Superoxide anion (SO) inhibits vascular relaxation and enhances vascular contraction. Although blood vessels possess the capacity to produce free radicals, including SO, the sources of SO are not clearly defined. The applicant's studies suggest that in normal rabbit aorta, a major source of SO production is unmasked by inhibition of endogenous superoxide dismutase. This SO is apparently derived from a novel enzymatic source which resembles but is distinct from neutrophil NADPH oxidase. The investigator has localized the activity within the membrane fraction of smooth muscle cells and adventitial cells, and has partially purified the protein. Preliminary data show that this source of SO is important in modulating vascular relaxation, since inhibition of SO production increases nitric oxide induced relaxations. A number of recent studies have shown an increased deleterious role of SO on the vasculature in angiotensin II (ANGII) hypertension and hypertension in general. More recently, a direct stimulation of this class of SO generating enzymes (NADH/NADPH oxidase) by angiotensin II (ANG II) was reported. The underlying hypothesis of this proposal is that ANGII dependent models of hypertension exhibit an increased activity and expression of the NADPH oxidase SO generating enzyme(s), which leads to increased SO generation and inhibits nitric oxide dependent relaxation and enhances endothelium dependent contraction contributing to the hypertension. This proposal will: (1) compare and contrast the vascular levels of SO and the activity and levels of the vascular NADPH oxidase source of SO in normotensive and ANG II-dependent and -independent hypertensive rabbits; (2) determine whether there is a contribution of NADPH oxidase derived SO to impaired relaxations and enhanced constrictions of blood vessels in ANG II- dependent hypertensive rabbits; (3) examine the effect of ANG II on NADPH oxidase levels and activity from cultured medial smooth muscle cells and adventitial cells. The proposed studies will determine whether ANG II and/or blood pressure elevation can stimulate the NADPH oxidase source of SO, and thereby exacerbate aberrant vascular tone.

描述：（改编自摘要）超氧阴离子 (SO) 抑制 舒张血管并增强血管收缩。 虽然有血 血管具有产生自由基的能力，包括 SO2、 SO 的来源没有明确定义。 申请人的研究表明 在正常兔子的主动脉中，SO 产生的主要来源是未被掩盖的 通过抑制内源性超氧化物歧化酶。 这显然是 源自一种类似但又不同的新型酶源 来自中性粒细胞 NADPH 氧化酶。 调查人员已定位 平滑肌细胞膜部分内的活性和 外膜细胞，并已部分纯化蛋白质。 初步的 数据表明，SO 的这种来源对于调节血管非常重要。 放松，因为抑制 SO 产生会增加一氧化氮 诱发松弛。 最近的一些研究表明， SO 对血管紧张素 II (ANGII) 血管系统的有害作用 高血压和一般高血压。 最近，直接 刺激此类 SO 生成酶（NADH/NADPH 氧化酶） 报道了血管紧张素 II (ANG II) 的作用。 基本假设为 该提议是 ANGII 依赖性高血压模型表现出 增加 NADPH 氧化酶 SO 生成的活性和表达 酶，导致 SO 生成增加并抑制硝酸 氧化物依赖性松弛并增强内皮依赖性 收缩导致高血压。 该提案将：(1) 比较和对比 SO 的血管水平和活性 正常血压和血压下血管 NADPH 氧化酶来源 SO 的水平 ANG II依赖性和非依赖性高血压兔； (2)确定 NADPH 氧化酶衍生的 SO 是否会导致受损 ANG II 中血管的松弛和增强的收缩 依赖性高血压兔； (3)考察ANG II对 培养的内侧平滑肌的 NADPH 氧化酶水平和活性 细胞和外膜细胞。 拟议的研究将确定是否 ANG II 和/或血压升高可以刺激 NADPH 氧化酶 SO 的来源，从而加剧异常的血管张力。