Central AT1 receptors and the integrated stress response.

点击翻译按钮获取中文摘要

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.