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年里，人们已经清楚地看到，活性氧基团(ROS)在许多血管疾病的发生中起着重要作用，包括动脉粥样硬化和高血压。在导致血管疾病的许多情况下，ROS的产生都会增加，包括高胆固醇血症、糖尿病、高血压、吸烟和衰老。也有证据表明，血管和非血管细胞中ROS的主要来源是NADPH氧化酶，它存在于许多相关的器官中，包括血管、肾脏和脑。初步研究表明，T细胞在血管紧张素II引起的高血压中是必不可少的，这可能解释了大脑等不同器官中NADPH氧化酶的激活如何导致高血压。血管紧张素II对中枢神经系统的影响早已被认为是持续性高血压的原因，最近的研究表明，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。该方案的总体目标是研究血管紧张素II的中枢神经系统作用是否有助于在血管紧张素II诱导的高血压过程中T细胞激活NADPH氧化酶和增加ROS的产生。我认为血管紧张素II对中枢神经系统的影响可以导致T细胞的激活。然后，激活的T细胞作用于血管，可能作用于肾脏，并通过细胞因子的释放刺激局部NADPH氧化酶，从而促进高血压。在这项提案中，我将特别关注血管紧张素II如何通过中枢神经系统调节这一过程，并将解决以下具体目标来检验这一假说。具体目标1将研究中枢神经系统在血管紧张素II诱导的高血压后T细胞激活中的作用。具体目标2将确定中枢神经系统和T细胞是否参与了血管紧张素11介导的高血压引起的NADPH氧化酶活性增加和活性氧物种(ROS)的产生。具体目标3将研究中枢神经系统和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。为了检查这些目的，我将对大脑的前腹侧第三脑室(AV3V)区域进行消融，并特别删除脑室周围器官中的NADPH氧化酶亚单位p22Phox。这一提议产生的数据将增强我们对高血压机制的了解，因为它与血管紧张素II有关，并将拓宽我们对炎症、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.