Central AT1 receptors and the integrated stress response.

描述（由申请人提供）：高血压影响着大约5000万美国人，这种疾病的进展显着增加了心血管疾病的风险。最近的临床研究表明，高血压也与精神健康障碍有关。具体而言，高血压增加焦虑症的风险，反之，焦虑症可预测高血压和心血管疾病的风险和严重程度。高血压的发病是由于肾素-血管紧张素系统（RAS）的过度活动，而焦虑的发生与下丘脑-垂体-肾上腺（HPA）轴的失调有关。RAS的效应肽血管紧张素II（ANGII）通过激活血管紧张素1型受体（ATIR）发挥其大部分生物学作用。有趣的是，ATIR在整个HPA轴中表达，并且新出现的证据表明ANGII是应激反应的重要介质。长期暴露于压力会上调HPA轴和RAS，从而对心血管和心理健康产生负面影响。鉴于慢性压力同样上调HPA轴和RAS，这些系统之间的相互作用可能是慢性压力对心理健康和心血管功能影响的基础。在这方面，我们最近的研究发现，循环ANGII通过刺激穹窿下的AT 1 R来驱动HPA轴的激活，穹窿下是一种结合血液传播激素的专门前脑结构。由于反复应激增加穹窿下器官中的ATIR表达，因此慢性应激可能增强循环ANGII对HPA轴的影响，从而诱导心血管和情感障碍。总的来说，这些研究表明，靶向RAS的治疗可能会影响焦虑等脑源性疾病的发作，因此，了解影响应激反应的中枢血管紧张素能通路非常重要。因此，本实验将利用反义寡脱氧核苷酸抑制实验大鼠穹窿下器官中AT 1 R的表达，以确定这些受体对心血管、HPA和急性和慢性应激行为反应的贡献。这些研究的目的是测试的总体假设，抑制穹窿下器官的AT 1 R将限制应激反应和减轻慢性应激暴露的有害后果。

DESCRIPTION (provided by applicant): Hypertension affects approximately 50 million Americans and progression of this disease significantly increases risk for cardiovascular disease. Recent clinical studies demonstrate, that hypertension also is associated with mental health disorders. Specifically, hypertension increases the risk of anxiety disorders, and inversely, anxiety disorders predict the risk and severity of hypertension and cardiovascular disease. While the onset of hypertension is attributed to over activity of the renin-angiotensin-system (RAS), the development of anxiety is associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. The effector peptide of the RAS, angiotensin II (ANGII), exerts the majority of its biological effects via activation of angiotensin type 1 receptors (ATI R). Interestingly, ATI R are expressed throughout the HPA axis and emerging evidence has implicated ANGII as an important mediator of the stress response. Chronic exposure to stress up-regulates the HPA axis and RAS, thereby negatively affecting cardiovascular and mental health. Given that chronic stress similarly up-regulates the HPA axis and the RAS, it is likely that an interaction between these systems underlies the effects that chronic stress has on mental health and cardiovascular function. In this regard, our recent study found that circulating ANGII drives activation of the HPA axis by stimulating AT1R in the subfornical, a specialized forebrain structure that binds blood-borne hormones. Because repeated stress increases ATI R expression in the subfornical organ, it is likely that chronic stress potentiates the influence of circulating ANGII on the HPA axis, thereby inducing cardiovascular and affective disorders. Collectively, these studies suggest that therapies targeting the RAS may influence the onset of brain-based disorders like anxiety, and therefore, it is important to understand the central angiotensinergic pathways that influence responses to stress. Accordingly, the proposed experiments will utilize antisense oligodeoxynucleotides to inhibit AT1R expression in the subfornical organ of laboratory rats to determine the contribution of these receptors to the cardiovascular, HPA and behavioral responses to acute and chronic exposure to stress. These studies are designed to test the overall hypothesis that inhibition of AT1R in the subfornical organ will limit stress responding and alleviate the deleterious consequences of chronic stress exposure.