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: 8509761
• 负责人: Irving H Zucker
• 金额: $ 38.76万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-05 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8509761
• 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; MAPK3 gene; 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）的交感神经流出调节是一个复杂的过程，涉及多种因素