Mitochondrial Redox Systems in Neurogenic Hypertension

神经源性高血压中的线粒体氧化还原系统

• 批准号: 7946689
• 负责人: Matthew C. Zimmerman
• 金额: $ 37.13万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7946689
• 关键词: Acute; Address; Angiotensin II; Antioxidants; Attenuated; Biochemical; Biology; Blood - brain barrier anatomy; Brain; Brain region; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Catalytic Domain; Cells; Chronic; Data; Development; Disease; Enzymes; Equilibrium; Figs - dietary; Free Radicals; Gene Transfer; Generations; Goals; Heart failure; Homeostasis; Hypertension; Infusion procedures; Lead; Link; Location; Manganese Superoxide Dismutase; Measures; Mediating; Mitochondria; Modeling; Molecular; NADPH Oxidase; Nerve; Neuraxis; Neurons; Organ; Outcome; Output; Oxidants; Oxidation-Reduction; Pathogenesis; Peptides; Physiological; Play; Potassium; Protein Isoforms; Protein Kinase C; Proteins; Publishing; Reactive Oxygen Species; Regulation; Renin-Angiotensin System; Reporting; Research; Role; Series; Signal Transduction; Site; Small Interfering RNA; Source; Subfornical Organ; Superoxides; System; Testing; Therapeutic; Training; Work; adenoviral-mediated; base; brain cell; experience; hypertension treatment; improved; mouse model; neurogenic hypertension; new therapeutic target; novel; novel therapeutics; overexpression; pressure; public health relevance; research study; response; therapeutic target

DESCRIPTION (provided by applicant): 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 blood-brain-barrier deficient brain regions, known as circumventricular organs (CVOs). Activation of the CVOs can alter central cardiovascular outputs including sympatho-excitation. To better understand the central actions of AngII in the development of neurogenic hypertension and to identify novel therapeutic targets of the disease, it is essential to investigate the intra- neuronal signaling mechanisms of AngII in the brain. Previously, we and others identified reactive oxygen species (ROS), particularly superoxide radicals (O2.-), generated by NADPH oxidase as important signaling intermediates in central neurons stimulated with AngII. However, additional sources of O2.-- including mitochondria, which are the primary sites for O2.- generation in most cells, have yet to be investigated. In addition, a potential link between NADPH oxidase and mitochondria-derived O2.- in the intra-neuronal signaling of AngII remains to be elucidated. Herein, we propose a series of molecular, biochemical, and integrative cardiovascular physiological experiments to test our hypothesis that a mitochondria-localized NADPH oxidase in AngII-sensitive neurons contributes to an increase in mitochondrial O2.-, which in turn mediates AngII-dependent hypertension by acting on redox-sensitive proteins known to control neuronal firing and sympatho-excitation. We will test this hypothesis in three Specific Aims. In Specific Aim 1, we will investigate the role of NADPH oxidase in producing mitochondria-localized O2.- in AngII-stimulated neurons. This aim builds upon our preliminary data showing that AngII increases mitochondrial O2.- in cultured neurons and that a NADPH oxidase catalytic subunit (Nox4) is present in mitochondria of neurons. In Specific Aim 2, we will examine the mechanisms by which mitochondrial-produced O2.- regulates AngII- induced neuronal activation. This aim is supported by our new preliminary data indicating that increased scavenging of mitochondrial O2.- via adenoviral-mediated overexpression of manganese superoxide dismutase (MnSOD), the O2.- scavenging enzyme specifically targeted to mitochondria, attenuates AngII- induced inhibition of neuronal potassium current. Finally, in Specific Aim 3, we will expand our previous observation that MnSOD overexpression in the brain inhibits the acute central AngII-induced pressor response by investigating the role of mitochondrial-produced O2.- in the brain in mediating the chronic sympatho-excitation and the development of hypertension in a mouse model of AngII-dependent neurogenic hypertension. These studies will provide new information on the intra-neuronal signaling mechanisms of AngII, and may identify mitochondrial-localized O2.- in neurons as important therapeutic targets in AngII-dependent neuro-cardiovascular diseases, such as hypertension. PUBLIC HEALTH RELEVANCE: Hypertension and heart failure and 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. By investigating and identifying the specific neuronal cell location where these oxidants are generated this project will advance opportunities to develop new therapeutics that may need to be targeted to specific cellular locations for the improved treatment of hypertension.

描述（由申请人提供）：脑血管紧张素II（ANGII）信号的失调与心血管疾病的发病机理有关，包括心力衰竭和高血压。循环水平增加的ANGII水平可以通过作用于血脑屏障缺乏大脑区域（称为脑室器官（CVO））来导致神经源性高血压的发展。 CVO的激活可以改变包括交感神经在内的中央心血管输出。为了更好地了解AngII在神经源性高血压发展中的中心作用并确定疾病的新型治疗靶标，必须研究大脑中Angii的神经元信号传导机制至关重要。以前，我们和其他人确定了由NADPH氧化酶产生的活性氧（ROS），特别是超氧化物自由基（O2.-），是用Angii刺激的中枢神经元中重要的信号传导中间体。但是，o2的其他来源 - 包括线粒体，这是O2的主要部位。-在大多数细胞中，尚未研究。此外，在Angii的神经内信号传导中，NADPH氧化酶与线粒体衍生的O2之间的潜在联系尚待阐明。 Herein, we propose a series of molecular, biochemical, and integrative cardiovascular physiological experiments to test our hypothesis that a mitochondria-localized NADPH oxidase in AngII-sensitive neurons contributes to an increase in mitochondrial O2.-, which in turn mediates AngII-dependent hypertension by acting on redox-sensitive proteins known to control neuronal firing和同情兴趣。我们将以三个具体目标来检验这一假设。在特定的目标1中，我们将研究NADPH氧化酶在AngII刺激的神经元中产生线粒体 - 定位的O2中的作用。这个目标建立在我们的初步数据的基础上，表明ANGII增加了线粒体O2。-在培养的神经元中，NADPH氧化酶催化亚基（NOX4）存在于神经元的线粒体中。在特定的目标2中，我们将检查线粒体生产的O2的机制。-调节血管诱导的神经元激活。这个目标得到了我们的新初步数据的支持，表明通过腺病毒介导的锰超氧化物歧化酶（MNSOD）的过表达增加了线粒体O2。-o2.- o2.-清除酶，靶向针对线粒体的靶向酶，降低了囊肿的抗抑制作用。最后，在特定的目标3中，我们将扩大先前的观察结果，即MNSOD在大脑中的过度表达通过研究线粒体生产的O2的作用来抑制急性中央Angii诱导的施加反应。---在介导慢性交感神经excitiation中的O.2中的作用。这些研究将提供有关ANGII的神经内信号传导机制的新信息，并可以鉴定线粒体 - 定位的O2。-在神经元中，神经元中是AngII依赖性神经心血管疾病的重要治疗靶标，例如高血压。 公共卫生相关性：高血压和心力衰竭，是两种与大脑异常刺激有关的心血管疾病。在这些心血管疾病中，在称为神经元的脑细胞中产生的自由基和氧化剂已被证明。通过研究和识别生成这些氧化剂的特定神经元细胞位置，该项目将促进开发新的疗法的机会，这些疗法可能需要针对特定​​的细胞位置，以改善高血压治疗。