Role of Redox-Mediated Activation of NFkappaB and AP-1 in Neurogenic Hypertension

氧化还原介导的 NFkappaB 和 AP-1 激活在神经源性高血压中的作用

• 批准号: 7081575
• 负责人: Robin L Davisson
• 金额: $ 44.69万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7081575
• 关键词: AP1 protein; angiotensin /renin /aldosterone hypertension; angiotensin II; bioluminescence; cardiovascular system; cell nucleus; central nervous system; essential hypertension; gene expression; genetically modified animals; hydrogen peroxide; laboratory mouse; molecular /cellular imaging; molecular pathology; neurogenic hypertension; nuclear factor kappa beta; oxidation reduction reaction; protein localization; protein structure function; superoxides; transcription factor; transfection

DESCRIPTION (provided by applicant): Human essential hypertension is characterized by sustained increases in sympathetic nerve activity. Exacerbation of angiotensin II (Ang-ll) signaling in the CNS has emerged as a primary culprit driving this chronic neuro-cardiovascular dysfunction, although the underlying molecular substrates are poorly understood. Recently we discovered that redox signaling in the CNS plays a primary role in the long-term effects of Ang-ll on blood pressure and sympathetic outflow. Furthermore, our studies demonstrate that chronic oxidative stress in central cardiovascular pathways is involved in the pathogenesis of hypertension and heart failure. The molecular mechanisms by which excessive oxidant production translates into long-lasting effects on central neural pathways controlling blood pressure are unknown. One way that transient ligand/receptor signals such as Ang-ll are transformed into long-term genetic changes is through activation of specific inducible transcription factors. Nuclear factor kappaB (NFkappaB) and activator protein 1 (AP-1) are important redox-sensitive transcription factors that mediate lasting changes in CNS function. Our preliminary in vivo bioluminescence imaging studies reveal a dramatic bi-phasic activation profile of NFkappaB and AP-1 in the brain of mice during the evolution of systemic Ang-ll "slow-pressor" hypertension. Building on this and also extending our studies to other models of brain Ang-ll-dependent hypertension, we will address the overall hypothesis that redox-mediated activation of NFkappaB and AP-1 in key CNS nuclei is causative molecular events in the pathogenesis of neurogenic hypertension and related autonomic dysfunction. Using a combination of live animal molecular imaging for serial tracking of NF?B and AP-1 activation, brain site-specific viral delivery of oxidant scavenging and dominant-suppressor genes, and integrative cardiovascular physiology in mice, we will perform the following studies: Aim 1) Spatiotemporally map and quantify NFkappaB and AP-1 activation in CNS cardiovascular nuclei of mice with Ang-ll slow-pressor, renovascular (2K1C) and life-long (human renin/human angiotensinogen) hypertension; Aim 2) Dissect the role of superoxide and H2O2 in Ang-ll-stimulated induction of NFkappaB and AP-1 activity in central cardiovascular circuits; Aim 3) Determine the functional role of central NFkappaB and AP-1 activation in the pathogenesis of neurogenic hypertension and related neuro-cardiovascular sequelae. This research has the potential to fundamentally advance our understanding of mechanisms linking the nervous system with cardiovascular disease, and could have important implications for developing novel therapeutic strategies for neurogenic hypertension and related disorders. A further strength of this project is the combination of live animal molecular imaging and sophisticated physiological genomic strategies.

描述（由申请人提供）：人类原发性高血压的特征是交感神经活动持续增加。CNS中血管紧张素II（Ang-II）信号传导的恶化已经成为驱动这种慢性神经-心血管功能障碍的主要原因，尽管对潜在的分子底物知之甚少。最近，我们发现CNS中的氧化还原信号传导在Ang-II对血压和交感神经流出的长期作用中起主要作用。此外，我们的研究表明，慢性氧化应激在中枢心血管通路参与高血压和心力衰竭的发病机制。过量氧化剂产生转化为对控制血压的中枢神经通路的持久影响的分子机制尚不清楚。瞬时配体/受体信号如Ang-II转化为长期遗传变化的一种方式是通过特异性诱导型转录因子的激活。核因子κ B（NF κ B）和激活蛋白1（AP-1）是重要的氧化还原敏感性转录因子，介导CNS功能的持久变化。我们的初步体内生物发光成像研究揭示了在全身性Ang-II“慢加压”高血压的演变过程中，小鼠脑中NF κ B和AP-1的戏剧性双相激活概况。在此基础上，并将我们的研究扩展到脑Ang-II依赖性高血压的其他模型，我们将解决以下总体假设：在关键CNS核中，NF κ B和AP-1的氧化还原介导的活化是神经源性高血压和相关自主神经功能障碍的发病机制中的致病分子事件。使用活体动物分子成像的组合，连续跟踪NF？B和AP-1的激活，脑内氧化剂清除和显性抑制基因的位点特异性病毒递送，以及小鼠的综合心血管生理学，我们将进行以下研究：目的1）时空定位和定量NF κ B B和AP-1在具有Ang-II慢升压、肾血管（2K 1C）和终身血管（2K 1C）的小鼠CNS心血管核中的激活。目的2）分析超氧化物和H_2O_2在Ang-II刺激的中枢心血管回路NF κ B和AP-1活性诱导中的作用;目的3）探讨中枢NF-κ B和AP-1活化在神经源性高血压及其相关神经心血管后遗症发病机制中的作用。这项研究有可能从根本上推进我们对神经系统与心血管疾病联系机制的理解，并可能对开发神经源性高血压和相关疾病的新治疗策略产生重要影响。该项目的另一个优势是活动物分子成像和复杂的生理基因组策略的结合。