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: 8102857
• 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/8102857
• 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; hypertensive heart disease; 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) 信号传导失调与心血管疾病（包括心力衰竭和高血压）的发病机制有关。 AngII 循环水平升高可通过作用于血脑屏障缺陷的大脑区域（称为心室周围器官 (CVO)）而导致神经源性高血压的发生。 CVO 的激活可以改变中枢心血管输出，包括交感神经兴奋。为了更好地了解 AngII 在神经源性高血压发展中的核心作用并确定该疾病的新治疗靶点，有必要研究 AngII 在大脑中的神经元内信号传导机制。此前，我们和其他人发现 NADPH 氧化酶产生的活性氧 (ROS)，特别是超氧自由基 (O2.-)，是 AngII 刺激的中枢神经元中重要的信号传导中间体。然而，其他 O2.- 来源（包括线粒体）尚未得到研究，线粒体是大多数细胞中 O2.- 生成的主要场所。此外，AngII 神经元内信号传导中 NADPH 氧化酶和线粒体来源的 O2.- 之间的潜在联系仍有待阐明。在此，我们提出了一系列分子、生化和综合心血管生理实验来检验我们的假设，即 AngII 敏感神经元中线粒体定位的 NADPH 氧化酶有助于线粒体 O2 的增加，进而通过作用于已知控制神经元放电的氧化还原敏感蛋白来介导 AngII 依赖性高血压。 和交感神经兴奋。我们将在三个具体目标中检验这一假设。在具体目标 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。这一目标建立在我们的初步数据之上，该数据表明 AngII 增加培养神经元中的线粒体 O2.-，并且 NADPH 氧化酶催化亚基 (Nox4) 存在于神经元线粒体中。在具体目标 2 中，我们将研究线粒体产生的 O2.- 调节 AngII 诱导的神经元激活的机制。我们新的初步数据支持了这一目标，表明通过腺病毒介导的锰超氧化物歧化酶（MnSOD）（专门针对线粒体的 O2.- 清除酶）过度表达来增加线粒体 O2.- 的清除，减弱 AngII 诱导的神经元钾电流的抑制。最后，在具体目标 3 中，我们将通过研究大脑中线粒体产生的 O2.- 在 AngII 依赖性神经源性高血压小鼠模型中介导慢性交感神经兴奋和高血压发展中的作用，扩展我们之前的观察结果，即大脑中 MnSOD 过度表达会抑制急性中枢 AngII 诱导的升压反应。这些研究将提供有关 AngII 神经元内信号传导机制的新信息，并可能将神经元中线粒体定位的 O2.- 确定为 AngII 依赖性神经心血管疾病（例如高血压）的重要治疗靶点。 公共卫生相关性：高血压和心力衰竭是与大脑异常刺激相关的两种心血管疾病。被称为神经元的脑细胞产生的自由基和氧化剂已被证明与这些心血管疾病有关。通过研究和识别产生这些氧化剂的特定神经元细胞位置，该项目将推动开发新疗法的机会，这些新疗法可能需要针对特定​​细胞位置来改善高血压的治疗。