Regulation of Central AT1R Expression in Heart Failure and Modulation by Exercise

心力衰竭中中枢 AT1R 表达的调节和运动的调节

基本信息

批准号：
7750832
负责人：
Irving H Zucker
金额：
$ 40.23万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7750832
关键词：
Address Angiopoietin-2 Angiotensin II Angiotensin II Receptor Angiotensin II Signaling Pathway Animal Experiments Animals Area Baroreflex Boxing Brain Brain Stem Cardiac Cardiovascular system Cell Culture Techniques Chronic Complex Conscious Data Deterioration Disease Down-Regulation ELK1 gene Elements Equilibrium Exercise FOS gene Feedback Generations Heart failure Human Hypothalamic structure Instruction Investigation JUN gene Lead Manganese Superoxide Dismutase Mediating Mediator of activation protein Membrane Molecular Molecular Genetics Mus N-terminal NF-kappa B Nerve Neuraxis Neurons Nucleus solitarius Oxidants Oxidases Oxidative Stress Pathway interactions Peptides Peptidyl-Dipeptidase A Performance Peripheral Peripheral Nervous System Phosphotransferases Physiological Play Process Protein Biosynthesis Proteins Publishing Rattus Reflex action Regulation Research Role Signal Pathway Signal Transduction Site Small Interfering RNA Solid Superoxides Technology Therapeutic Training Transcription Factor AP-1 Transcriptional Regulation Transgenic Mice United States Up-Regulation Viral Work base body system elk-1 protein hemodynamics inhibitor/antagonist mouse model novel overexpression receptor receptor expression research study transcription factor

项目摘要

The regulation of sympathetic outflow in chronic heart failure (CHF) is a complex process involving a variety of central and peripheral mediators. Angiotensin II (Ang II) in the central nervous system plays a pivotal role in determining the discharge sensitivity of neurons responsible for generating sympathetic outflow. Critical to the action of Ang II is the predominant receptor type, the ATi receptor (ATiR). Studies carried out in this project over the past 5 years have clearly shown an upregulation of ATiR expression at both the protein and message levels in various areas of the medulla and its role in increasing reactive oxidant species (ROS). Furthermore, we have shown an important modulation of ATiR expression and sympathetic nerve activity by exercise training (ExT) in the CHF state. In the current proposal we extend our investigation into the regulation of ATiR expression in the rostral ventrolateral medulla (RVLM). We now focus on transcriptional regulation of ATiR expression by two ubiquitous transcription factors. Activator Protein 1 (AP-1) and Nuclear Factor Kappa B (NFkB). In Specific Aims 1 and 2 we propose that CHF modulates proteins necessary for the generation of AP-1 in the RVLM. These proteins include c-fos, c-jun and Jun N terminal Kinase (JNK). Furthermore, we will determine the role of NFkB and its inhibitor, IkB and its kinase (IkK) in activation of NFkB in CHF. We also provide evidence for activation of an additional transcription factor, Elk-1 which may be critical to ATiR regulation. The roles of ROS and ExT will be investigated in whole animal experiments as well as in neuronal cell cultures. In these experiments we will make use of chronic sympathetic nerve recordings in conscious animals and molecular suppression experiments using inhibitors and siRNA technology. The level of Ang II in the brain is dependent on its conversion from Ang I by Angiotensin Converting Enzyme (ACE) and its degradation to Ang (1-7) by ACE2. Therefore, in Specific Aims 3 and 4 we investigate the role of central ACE and overexpression of ACE2 on sympathetic nerve activity (SNA), baroreflex function and cardiac function in rats and mice with CHF. Based on our preliminary data we will investigate the effects of ExT on the central expression of ACE and ACE2. Using pharmacological inhibitors we will determine the role of ACE2 and Ang (1-7) on SNA in animals with CHF. In these two Specific Aims we will utilize viral tranfection of the RVLM and NTS in order to chronically over express ACE2. Furthermore, we will use a novel transgenic mouse model that over expresses human ACE2 selectively in neurons (syn- hACE2) to evaluate ACE2 on baroreflex function. SNA, ATiR and cardiac function in CHF. RELEVANCE (See Instructions): Over 5 million people are afflicted with chronic heart failure in the United States. The sequelae of this disorder, such as sympatho-excitation, initiate a positive feedback loop that evokes further deterioration of cardiac function. It is critical to understand the neuronal mechanisms responsible for sympatho-excitation in CHF. Furthermore, this research will determine the mechanism that may be partly responsible for the therapeutic benefits of exercise training on sympathetic outflow in CHF. PROJECT/PERFORIVIANCE SITE(S) (if additional space is needed, use Project/Performance

慢性心力衰竭（CHF）交感神经流出的调节是一个复杂的过程，涉及多种因素中枢和外周介质。血管紧张素II（Ang II）在中枢神经系统中起着举足轻重的作用确定负责产生交感神经流出的神经元的放电敏感性。至关重要 Ang II 的作用是主要受体类型，即 ATi 受体 (ATiR)。在这方面开展的研究过去 5 年的项目清楚地表明 ATiR 表达在蛋白质和髓质各个区域的信息水平及其在增加活性氧化剂（ROS）中的作用。此外，我们还发现 ATiR 表达和交感神经活动的重要调节作用是通过 CHF状态下的运动训练（ExT）。在当前的提案中，我们将调查范围扩大到延髓头端腹外侧 (RVLM) 中 ATiR 表达的调节。我们现在专注于转录两个普遍存在的转录因子对 ATiR 表达的调节。激活蛋白 1 (AP-1) 和核因子 Kappa B (NFkB)。在具体目标 1 和 2 中，我们提出 CHF 调节 RVLM 中 AP-1 的生成。这些蛋白质包括 c-fos、c-jun 和 Jun N 末端激酶 (JNK)。此外，我们将确定 NFkB 及其抑制剂、IkB 及其激酶 (IkK) 在激活 NFkB 单位为 CHF。我们还提供了另一个转录因子 Elk-1 激活的证据，该因子可能对 ATiR 监管至关重要。 ROS 和 ExT 的作用将在整个动物实验中进行研究以及神经元细胞培养物。在这些实验中，我们将利用慢性交感神经使用抑制剂和 siRNA 对有意识的动物进行录音和分子抑制实验技术。大脑中 Ang II 的水平取决于血管紧张素从 Ang I 的转化转化酶 (ACE) 及其被 ACE2 降解为 Ang (1-7)。因此，在具体目标 3 和 4 中我们研究中枢 ACE 和 ACE2 过度表达对交感神经活动 (SNA) 的作用， CHF 大鼠和小鼠的压力感受反射功能和心脏功能。根据我们的初步数据，我们将研究 ExT 对 ACE 和 ACE2 中枢表达的影响。使用药物抑制剂我们将确定 ACE2 和 Ang (1-7) 对患有 CHF 的动物的 SNA 的作用。在这两个具体目标中我们将利用 RVLM 和 NTS 的病毒转染来长期过度表达 ACE2。此外，我们将使用一种新型转基因小鼠模型，该模型在神经元中选择性过度表达人类 ACE2（syn- hACE2) 来评估 ACE2 对压力感受反射功能的影响。 CHF 的 SNA、ATiR 和心脏功能。相关性（参见说明）：在美国有超过 500 万人患有慢性心力衰竭。这件事的后遗症紊乱，例如交感神经兴奋，会启动一个正反馈循环，引起进一步恶化心脏功能。了解负责交感神经兴奋的神经元机制至关重要瑞士法郎。此外，这项研究将确定可能部分导致这一现象的机制。运动训练对 CHF 交感神经流出的治疗效果。项目/绩效站点（如果需要额外空间，请使用项目/绩效