HYPERTENSION AND VASCULAR SUPEROXIDE GENERATION

高血压和血管超氧化物生成

• 批准号: 2378873
• 负责人: Patrick J Pagano
• 金额: $ 11.76万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 1998-09-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2378873
• 关键词: NAD(P)H dehydrogenase; angiotensin /renin /aldosterone hypertension; angiotensin II; enzyme activity; enzyme mechanism; hypertension; laboratory rabbit; muscle tone; oxidative stress; superoxide dismutase; superoxides; tissue /cell culture; vascular smooth muscle; vasomotion

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：(摘自摘要)超氧阴离子(SO)抑制 血管松弛，增强血管收缩。虽然鲜血 血管具有产生自由基的能力，包括SO、 SO的来源没有明确的定义。申请者的研究表明 在正常的兔主动脉中，产生SO的一个主要来源已被揭开 通过抑制内源性超氧化物歧化酶。很明显，这就是 来自一种新的酶来源，类似但不同 来自中性粒细胞NADPH氧化酶。调查员已经将 平滑肌细胞膜组分内的活性和 外膜细胞，并对该蛋白进行了部分纯化。初步 数据显示，这种SO来源在调节血管功能方面很重要 松弛，因为抑制SO的产生增加了一氧化氮 诱导放松。最近的一些研究表明， SO在血管紧张素II(AngII)中的有害作用 高血压和一般的高血压。最近，一项直接的 对这类生硫酶(NADH/NADPH氧化酶)的刺激 血管紧张素II(Ang II)的作用已有报道。潜在的假设是 这一建议是血管紧张素转换酶依赖性高血压模型表现出 由此产生的NADPH氧化酶的活性和表达增加 酶(S)，导致SO生成增加并抑制一氧化氮 氧化物依赖性松弛与增强内皮依赖性 收缩会导致高血压。这项建议将：(1) 比较和对比血管内皮细胞水平和血管内皮细胞活性 正常血压和高血压患者血管组织中NADPH氧化物源的水平 血管紧张素Ⅱ依赖和非依赖性高血压兔；(2)测定 因此衍生的NADPH氧化酶是否对受损的人有贡献 血管的松弛和增强的收缩。 (3)观察血管紧张素转换酶II对血管紧张素转换酶的影响。 培养的中膜平滑肌NADPH氧化酶水平和活性 细胞和外膜细胞。拟议的研究将确定 Ang II和/或血压升高可刺激NADPH氧化酶 SO的来源，从而加剧异常的血管张力。