The Central Nervous System and T-Cells in Angiotensin II Induced Hypertension

描述（由申请人提供）：在过去的20年中，已经清楚的是，活性氧（ROS）在许多血管疾病的发生中是重要的，包括动脉粥样硬化和高血压。ROS的产生在引起血管疾病的许多条件下增加，包括高胆固醇血症、糖尿病、高血压、吸烟和衰老。同样明显的是，血管和非血管细胞中ROS的主要来源是NADPH氧化酶，其存在于许多相关器官中，包括血管、肾和脑。初步研究表明，T细胞对于血管紧张素II引起的高血压是必不可少的，并且可以解释各种器官（如大脑）中NADPH氧化酶的激活如何导致高血压。血管紧张素II对中枢神经系统的作用长期以来被认为是导致持续性高血压的原因，最近其他人的研究表明，血管紧张素II通过ROS介导的机制引起高血压，涉及脑室周器官中的NADPH氧化酶。本提案的总体目标是研究血管紧张素II的CNS作用是否有助于血管紧张素II诱导的高血压期间NADPH氧化酶的T细胞活化和ROS的产生增加。我认为血管紧张素II对中枢神经系统的影响可以导致T细胞活化。然后，活化的T细胞作用于血管和可能的肾脏，并通过细胞因子释放刺激促进高血压的局部NADPH氧化酶。在本提案中，我将特别关注血管紧张素II如何通过中枢神经系统介导这一过程，我将讨论以下具体目标来验证这一假设。具体目标1将检查CNS在血管紧张素II诱导的高血压后T细胞活化中的作用。具体目标2将确定CNS和T细胞是否有助于由血管紧张素II介导的高血压引起的NADPH氧化酶活性和活性氧（ROS）产生的增加。具体目标3将检查CNS和T细胞在血管紧张素II诱导的高血压引起的血管功能障碍中的作用。为了检查这些目标，我将进行消融的前腹侧第三脑室（AV3V）区域的大脑，也专门删除NADPH氧化酶亚基p22phox在室周器官。从这个提议中产生的数据将增强我们对高血压机制的认识，因为它与血管紧张素II有关，并将扩大我们对炎症，ROS和血管疾病之间关系的理解。

DESCRIPTION (provided by applicant): During the past 2 decades, it has become clear that reactive oxygen species (ROS) are important in the genesis of numerous vascular diseases, including atherosclerosis and hypertension. The production of ROS is increased in numerous conditions that cause vascular disease, including hypercholesterolemia, diabetes, hypertension, smoking and aging. It has also become evident that the major sources of ROS in vascular and non-vascular cells are the NADPH oxidases which are present in many relevant organs, including the vessel, the kidney and the brain. Preliminary studies suggest that the T cell is essential for hypertension caused by angiotensin II and may explain how activation of the NADPH oxidases in various organs, such as the brain leads to hypertension. The effects of angiotensin II on the central nervous system have long been known to contribute to sustained hypertension and recent work from others suggests that angiotension II causes hypertension via a ROS mediated mechanism, involving the NADPH oxidase in the circumventricular organs of the brain. The overall goal of this proposal is to investigate whether the CNS actions of angiotensin II contributes to T cell activation of NADPH oxidases and increased generation of ROS during angiotensin II induced hypertension. I propose that the effects of angiotensin II on the central nervous system can lead to T cell activation. Activated T cells then act on vessels and likely the kidney and via cytokine release stimulate local NADPH oxidases that promote hypertension. In this proposal, I will specifically focus on how angiotensin II may mediate this process via the CNS and I will address the following specific aims to test this hypothesis. Specific aim 1 will examine the role of the CNS in T-cell activation following angiotensin II induced hypertension. Specific aim 2 will determine whether the CNS and the T cell contribute to increased NADPH oxidase activity and reactive oxygen species (ROS) generation caused by angiotensin ll-mediated hypertension. Specific aim 3 will examine the role of the CNS and the T cell in contributing to the vascular dysfunction caused by angiotensin II induced hypertension. To examine these aims I will perform ablation of the anteroventral third ventricle (AV3V) region of the brain and also specifically delete the NADPH oxidase subunit p22phox in the circumventricular organs. The data generated from this proposal will enhance our knowledge of the mechanisms of hypertension as it relates to angiotensin II and will broaden our understanding of the relationships between inflammation, ROS and vascular disease.