ROLE OF MITOCHONDRIAL-PRODUCED ROS IN NEUROGENIC HYPERTENSION

线粒体产生的 ROS 在神经源性高血压中的作用

• 批准号: 7960361
• 负责人: Matthew C. Zimmerman
• 金额: $ 16.63万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960361
• 关键词: Angiotensin II; Antioxidants; Baroreflex; Biochemical; Biological; Biology; Blood - brain barrier anatomy; Brain; Brain region; Cardiovascular Diseases; Cardiovascular system; Cell Culture Techniques; Cells; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Free Radicals; Funding; Gene Transfer; Generations; Goals; Grant; Heart failure; Hypertension; In Vitro; Institution; Lead; Location; Measures; Mediating; Mitochondria; Modeling; Molecular; NADPH Oxidase; Neuraxis; Neurons; Organ; Output; Oxidants; Oxidation-Reduction; Pathogenesis; Physiological; Play; Reactive Oxygen Species; Research; Research Personnel; Resources; Role; Series; Signal Transduction; Site; Source; Techniques; Testing; United States National Institutes of Health; Vasopressins; adenoviral-mediated; brain cell; chronotropic; in vivo; mouse model; neurogenic hypertension; novel; overexpression; prevent; research study; therapeutic target

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dysregulation of brain angiotensin II (AngII) signaling is implicated in the pathogenesis of cardiovascular diseases, including heart failure and hypertension. Increased circulating levels of AngII can lead to the development of neurogenic hypertension by acting on specialized brain regions known as circumventricular organs, which lack a blood-brain-barrier, and altering central cardiovascular outputs including sympathoexcitation, release of vasopressin, and dampening of baroreflexes. To better understand the central actions of AngII in the development of neurogenic hypertension and to identify novel, central therapeutic targets of the disease, it is essential to investigate the signaling mechanisms of AngII in the central nervous system (CNS). Previously, reactive oxygen species (ROS) generated by NADPH oxidase have been identified as important signaling intermediates in central AngII-mediated cardiovascular effects. Although NADPH oxidase has been shown to be a critical source of ROS, additional sources including mitochondria, which are the primary sites for ROS generation in most cells, have yet to be investigated. Herein, we propose a series of in vitro molecular biological and biochemical studies and in vivo integrative cardiovascular physiological experiments to test the novel hypothesis that mitochondrial-produced ROS play a fundamental role in brain angiotensinergic signaling, and that overexpression of mitochondrial-targeted antioxidants in CNS cardiovascular control regions ameliorates neurogenic hypertension. Using CNS-derived primary neurons, as well as an AngII-sensitive neuronal cell culture model we will measure ROS levels specifically in mitochondria following AngII stimulation. In addition, we will use adenoviral-mediated gene transfer of mitochondrial-targeted antioxidants to examine the effects of mitochondrial-produced ROS on the chronotropic action of AngII in neurons using electrophysiological techniques. Finally, using an experimental mouse model of AngII-dependent neurogenic hypertension we will determine the role of mitochondrial-produced ROS in the CNS in the pathogenesis of the disease. These studies will provide new information on the intra-neuronal signaling mechanisms of AngII, and may identify mitochondrial-produced ROS as important therapeutic targets in neurogenic hypertension. Lay Description: Heart failure and hypertension are two cardiovascular diseases associated with abnormal stimulation in the brain. Free radicals and oxidants produced in brain cells called neurons have been shown to be involved in these cardiovascular diseases. The primary goal of this study is to use antioxidants, which are found in a specific cellular location (mitochondria), to prevent the development of hypertension.

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