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

描述(申请人提供)：高血压(HTN)是全球头号可归因性死亡风险因素，导致缺血性心脏病、心力衰竭、中风和慢性肾脏疾病的发病率和死亡率增加。NADPH氧化酶家族产生的ROS参与HTN的病理生理过程。然而，一个关键的悬而未决的问题是，哪种细胞类型在调节血压(BP)中起关键作用，以及相关的酶/信号通路是什么。我们实验室的初步数据表明，在血管紧张素II(Ang II)诱导的HTN中，T细胞通过T细胞NADPH氧化酶是必不可少的。我们提出了一个模型，在这个模型中，Ang II直接作用于T细胞，并具有中枢作用，导致T细胞激活，然后激活的T细胞通过渗透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。在这项研究中，我们将探讨T细胞NADPH氧化酶和血管NADPH氧化酶在血管紧张素转换酶诱导的HTN中的作用。具体目的1.明确T细胞NADPH氧化酶在Ang II靶向敲除T细胞p22Phox诱导的HTN中的作用。使用转基因小鼠模型，我们将创造出只在T细胞中缺失p22Phox的小鼠，p22Phox是大多数类型NADPH氧化酶的关键成分。然后我们将确定血管紧张素转换酶II对血压反应、主动脉超氧化物生成和血管反应性的影响。具体目的2.通过检测T细胞NADPH氧化酶对T细胞进入血管壁的影响，进一步阐明T细胞介导HTN的机制。我们实验室的初步数据显示，Ang II显著增加外膜和外膜脂肪中的T细胞数量，这种增加在所有细胞中NADPH氧化酶缺陷的小鼠中都减弱。在这个目的中，我们将使用靶向缺失T细胞中的p22Phox的小鼠来确定其对T细胞渗透的影响。具体目的3.明确血管平滑肌细胞(VSMC)NADPH氧化酶和内皮细胞(EC)NADPH氧化酶在Ang II通过条件性靶向敲除VSMC或ECs中的p22Phox诱导HTN和T细胞浸润中的作用。这项研究计划中描述的实验将进一步加深我们对ROS促进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。这项提案中描述的研究将进一步加深我们对高血压发生过程中所涉及的细胞类型和途径的了解，并有望导致对这种疾病的更好治疗。

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.