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

• 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
• 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

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）时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（AngII）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。的关键 血管紧张素II的作用是主要的受体类型，ATi受体（ATiR）。在这方面进行的研究 在过去5年的研究项目中，已经清楚地显示了ATiR在蛋白质和 信息水平在不同领域的髓质和它的作用，增加活性氧化物（ROS）。 此外，我们已经显示了ATiR表达和交感神经活性的重要调节， CHF状态下的运动训练（ExT）。在目前的建议中，我们将调查扩展到 ATiR在延髓头端腹外侧区（RVLM）表达的调节。我们现在关注转录 ATiR的表达受两种普遍存在的转录因子的调节。激活蛋白1（AP-1）与核 因子κ B（NF κ B）。在具体目标1和2中，我们提出CHF调节蛋白质， 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）在活化细胞中的作用。 NFkB单位：CHF。我们还提供了一个额外的转录因子Elk-1的激活的证据， 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， 以及在神经元细胞培养物中。在这些实验中，我们将利用慢性交感神经 在清醒动物中的记录和使用抑制剂和siRNA的分子抑制实验 技术.脑中Ang Ⅱ的水平依赖于血管紧张素Ⅱ对Ang Ⅰ的转化 血管紧张素转换酶（ACE）及其降解为血管紧张素（1-7）的ACE 2。具体目标3和4 我们研究了中枢ACE和ACE 2过表达对交感神经活动（SNA）的作用， CHF大鼠和小鼠的压力反射功能和心功能。根据我们的初步数据， 探讨ExT对ACE和ACE 2中枢表达的影响。使用药物抑制剂 我们将确定ACE 2和Ang（1-7）在CHF动物SNA中的作用。在这两个具体目标中 我们将利用RVLM和NTS的病毒转染以长期过表达ACE 2。此外，委员会认为， 我们将使用一种新的转基因小鼠模型，该模型在神经元中选择性地过表达人ACE 2（syn， hACE 2）评价ACE 2对压力感受性反射功能的影响。CHF患者SNA、ATiR与心功能的关系 相关性（见说明）： 在美国，超过500万人患有慢性心力衰竭。这件事的后遗症 疾病，如交感神经兴奋，启动一个积极的反馈循环，引起进一步恶化， 心脏功能了解交感神经兴奋的神经机制是至关重要的， 瑞士法郎。此外，这项研究将确定可能部分负责的机制， 运动训练对CHF交感神经流出的治疗作用 项目/验收现场（如果需要额外空间，请使用项目/性能