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(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。中枢神经系统中血管紧张素II(Ang-11)信号的恶化已成为导致这种慢性神经心血管功能障碍的主要原因，尽管其潜在的分子底物尚不清楚。最近我们发现，中枢神经系统中的氧化还原信号在Ang-11对血压和交感神经流出的长期影响中起主要作用。此外，我们的研究表明，中枢心血管通路的慢性氧化应激参与了高血压和心力衰竭的发病机制。过量的氧化剂产生转化为对控制血压的中枢神经通路的长期影响的分子机制尚不清楚。像Ang-11这样的瞬时配体/受体信号转化为长期遗传变化的一种方式是通过激活特定的可诱导转录因子。核因子kappaB(NFkappaB)和激活蛋白1(AP-1)是重要的氧化还原敏感转录因子，介导中枢神经系统功能的持续变化。我们初步的活体生物发光成像研究显示，在系统性血管紧张素Ⅱ“慢升压性”高血压的演变过程中，NFkappaB和AP-1在小鼠大脑中呈现出戏剧性的双相激活。在此基础上，并将我们的研究扩展到其他脑血管依赖性高血压模型，我们将解决氧化还原介导的中枢神经系统关键核团NFkappaB和AP-1激活是神经源性高血压和相关自主神经功能障碍发病机制中的致病分子事件的总体假设。我们将利用活体动物分子成像技术对NFkappaB和AP-1的激活进行连续示踪，结合脑内定点病毒传递氧化剂清除和显性抑制基因，以及综合心血管生理学，进行以下研究：目的1)时空定位和定量研究Ang-11慢升压型、肾血管型(2K1C)和终生型(人肾素/人血管紧张素原)高血压小鼠中枢心血管核团NFkappaB和AP-1的激活；目的3)探讨中枢NFkappaB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提高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具有重要意义。该项目的另一个优势是将活体动物分子成像和复杂的生理基因组策略相结合。