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（由申请人提供）：高血压 (HTN) 是全球第一大死亡危险因素，导致缺血性心脏病、心力衰竭、中风和慢性肾病的发病率和死亡率增加。 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，一个尚未解决的关键问题是哪种细胞类型对于血压（BP）的调节至关重要以及所涉及的相关酶/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 氧化酶对于血管紧张素 II (Ang II) 诱导的 HTN 至关重要。我们提出了一个模型，其中 Ang II 直接作用于 T 细胞，并具有导致 T 细胞激活的中心效应，然后激活的 T 细胞通过浸润和细胞因子释放作用于血管壁和肾脏，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 p22phox，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，我们将创建仅在 T 细胞中删除 p22phox（大多数类型 NADPH 氧化酶的关键成分）的小鼠。然后我们将确定 Ang II 对血压反应、主动脉超氧化物产生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机制。我们实验室的初步数据表明，Ang II 显着增加了外膜和外膜周围脂肪中 T 细胞的数量，而在所有细胞中 NADPH 氧化酶缺陷的小鼠中，这种增加减少了。为此，我们将使用 T 细胞中 p22phox 的靶向删除小鼠来确定对 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 p22phox，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。高血压是一种常见疾病，也是心脏病、中风和肾脏疾病的主要危险因素。该提案中描述的研究将进一步加深我们对高血压发展所涉及的细胞类型和途径的了解，并有望为这种情况提供更好的治疗方法。