Role of T Cell and Vascular NADPH Oxidases in Angiotensin II Induced Hypertension

T 细胞和血管 NADPH 氧化酶在血管紧张素 II 诱导的高血压中的作用

• 批准号: 7693802
• 负责人: Meenakshi Swaminathan Madhur
• 金额: $ 5.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7693802
• 关键词: Address; Adoptive Transfer; Affect; Angiotensin II; B-Lymphocytes; Blood Pressure; Blood Vessels; CCR5 gene; CD44 gene; Cell surface; Cells; Cessation of life; Chronic Kidney Failure; Code; Data; Development; Endothelial Cells; Equilibrium; Essential Hypertension; Family; Fatty acid glycerol esters; Functional disorder; Heart Diseases; Heart failure; Hypertension; Infiltration; Infusion procedures; Kidney; Kidney Diseases; Knock-out; Knockout Mice; Laboratories; Lead; Ligands; Mediating; Modeling; Morbidity - disease rate; Mus; Myocardial Ischemia; Myosin Heavy Chains; NADP; NADPH Oxidase; Neuraxis; Organ; Oxidases; Pathway interactions; Production; Reactive Oxygen Species; Research Proposals; Risk Factors; Role; Signal Pathway; Site; Smooth Muscle Myocytes; Smooth Muscle Myosins; Stroke; Superoxides; T-Cell Activation; T-Lymphocyte; Tamoxifen; Time; Transgenic Mice; Tunica Adventitia; United States; blood pressure regulation; cardiovascular risk factor; cell type; chemokine receptor; cytokine; human CYBA protein; mortality; mouse model; promoter; research study; response

DESCRIPTION (provided by applicant): Hypertension (HTN) is the number one attributable risk factor for death worldwide leading to increased morbidity and mortality from ischemic heart disease, heart failure, stroke, and chronic kidney disease. Reactive oxygen species (ROS) produced by the NADPH family of oxidases contributes to the pathophysiology of HTN. However, a key unresolved issue is which cell type is critical in the regulation of blood pressure (BP) and what is the relevant enzymatic/signaling pathways involved. Preliminary data from our lab suggests that T cells via a T cell NADPH oxidase are essential for HTN induced by angiotensin II (Ang II). We propose a model in which Ang II acts directly on T cells and has central effects which lead to T cell activation and that activated T cells then act on vessel walls and the kidney via infiltration and cytokine release to stimulate local NADPH oxidases which in turn promote HTN. In this proposal, we will investigate the role of the T cell NADPH oxidase vs vascular NADPH oxidases in Ang II induced HTN by addressing the following specific aims. Specific Aim 1. Define the role of the T cell NADPH oxidase in Ang II induced HTN by targeted knockout of the T cell p22phox. Using transgenic mouse models, we will create mice in which p22phox, a critical component of most types of NADPH oxidase, is deleted in T cells only. We will then determine the effect of Ang II on BP response, aortic superoxide production, and vascular reactivity. Specific Aim 2. Further elucidate the mechanism of T cell mediated HTN by determining the effect of the T cell NADPH oxidase on T cell infiltration into the vessel wall. Preliminary data from our lab showed that Ang II markedly increased the number of T cells in the adventitia and periadventitial fat and that this increase was diminished in mice with defective NADPH oxidase in all cells. In this aim, we will use mice with targeted deletion of p22phox in T cells only to determine the effect on T cell infiltration. Specific Aim 3. Define the role of the vascular smooth muscle cell (VSMC) NADPH oxidase vs the endothelial cell (EC) NADPH oxidase in Ang II induced HTN and T cell infiltration by conditional, targeted knockout of p22phox in VSMCs or ECs. The experiments described in this research proposal will further our understanding of the mechanisms by which ROS contribute to hypertension. High blood pressure is a common condition and major risk factor for heart disease, stroke, and kidney disease. The studies described in this proposal will further our understanding of the cell types and pathways involved in the development of high blood pressure and hopefully lead to better treatments for this condition.

描述（由申请方提供）：高血压（HTN）是全球范围内导致缺血性心脏病、心力衰竭、卒中和慢性肾脏疾病发病率和死亡率增加的头号死亡归因风险因素。由NADPH氧化酶家族产生的活性氧（ROS）有助于HTN的病理生理学。然而，一个关键的未解决的问题是哪种细胞类型在血压（BP）的调节中至关重要，以及涉及的相关酶/信号通路是什么。我们实验室的初步数据表明，T细胞通过T细胞NADPH氧化酶对血管紧张素II（Ang II）诱导的HTN至关重要。我们提出了一种模型，其中Ang II直接作用于T细胞，并具有导致T细胞活化的中枢效应，然后活化的T细胞通过浸润和细胞因子释放作用于血管壁和肾脏，以刺激局部NADPH氧化酶，进而促进HTN。在本提案中，我们将通过解决以下具体目标来研究T细胞NADPH氧化酶与血管NADPH氧化酶在Ang II诱导的HTN中的作用。具体目标1.通过靶向敲除T细胞p22 phox，确定T细胞NADPH氧化酶在Ang II诱导的HTN中的作用。使用转基因小鼠模型，我们将创建p22 phox，大多数类型的NADPH氧化酶的关键组成部分，只在T细胞中删除的小鼠。然后，我们将确定血管紧张素II对血压反应，主动脉超氧化物生成和血管反应性的影响。具体目标2。通过测定T细胞NADPH氧化酶对T细胞浸润血管壁的影响，进一步阐明T细胞介导的HTN的机制。我们实验室的初步数据显示，血管紧张素II显着增加外膜和外膜周围脂肪中的T细胞数量，并且在所有细胞中具有缺陷NADPH氧化酶的小鼠中，这种增加减少。为此，我们将使用仅在T细胞中靶向缺失p22 phox的小鼠来确定对T细胞浸润的影响。具体目标3。通过条件性靶向敲除VSMC或EC中的p22 phox，确定血管平滑肌细胞（VSMC）NADPH氧化酶与内皮细胞（EC）NADPH氧化酶在Ang II诱导的HTN和T细胞浸润中的作用。本研究提案中描述的实验将进一步加深我们对ROS导致高血压的机制的理解。高血压是一种常见的疾病，也是心脏病、中风和肾脏疾病的主要危险因素。本提案中描述的研究将进一步加深我们对高血压发展中涉及的细胞类型和途径的理解，并有望为这种疾病提供更好的治疗方法。