Aging, the Baroreflex and Ang-(1-7) Receptors

衰老、压力反射和 Ang-(1-7) 受体

• 批准号: 6853112
• 负责人: Debra I Diz
• 金额: $ 18.36万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853112
• 关键词: age difference; aging; angiotensin II; angiotensin receptor; angiotensinogen; angiotensins; baroreflex; heart function; hypertension; insulin; laboratory mouse; laboratory rat; peptide hormone metabolism; receptor expression; renin angiotensin system

Aging is typified by progressive impairments in cardiovascular regulation that may include increased sympathetic outflow, reduced vagal activity and reduced vascular distensibility. These cardiovascular changes are also associated with decreased activity of the renin-angiotensin (Ang) system (RAS) and insulin resistance. The over-arching goal of Project 4 is to define how insulin and specific components of the RAS act together as major contributors to altered cardiovascular regulation that ultimately lead to elevated systolic pressure and exacerbation of hyperinsulinemia and hyperglycemia during the course of aging. We focus on the opposing actions of Ang II and Ang-(1-7) in the nucleus of the solitary tract (nTS) to modulate the baroreceptor reflex control of sympathetic and parasympathetic outflow. The investigations will define how insulin may act in concert with or opposition to these two peptides in neural regulation of autonomic outflow via actions at cardiovascular relevant regions of the medulla oblongata and hypothalamus. Our experimental strategy will draw upon the combined expertise of members of the Project to define the neural systems, peptide receptor pathways, and metabolic components that interact to account for modification of cardiovascular regulation during aging. Specific Aim 1 investigates the hypothesis that the role of endogenous Ang-(1-7) to facilitate baroreceptor reflex function diminishes with aging, such that the effects of Ang II and insulin are unopposed, thereby contributing to reduced cardiac vagal outflow, enhanced sympathetic outflow, and hypertension. Experiments will focus on the nTS, paraventricular nucleus of the hypothalamus, and rostral ventrolateral medulla as key sites in the brain where actions of Ang peptides and insulin change during the aging process. As one mechanism contributing to the altered roles of Ang peptides and insulin during aging Specific Aim 2 will test the hypothesis that Ang-(1-7) in brain tissue diminishes with age, leading to a shift in the function or expression of Ang II and insulin. Since receptors constitute a key functional component in the aforementioned central regulation of cardiovascular function during aging, Specific Aim 3 will assess the hypothesis that Ang II and Ang-(1-7) receptors undergo a dynamic regulation, in part, determined by alterations in the tissue levels of these two peptides. In particular, the proposed experiments will establish the functional interactions that develop between the AT1b receptor and the mas orphan receptor as key elements responsive to Ang-(1-7). The proposed experiments utilize a transgenic rat model deficient in the production of brain angiotensinogen (ASrAogen), which we show does NOT exhibit cardiovascular impairments over the same time frame typically associated with aging in Sprague-Dawley rats.

衰老的典型特征是心血管调节逐渐受损，可能包括交感神经流出增加、迷走神经活动减少和血管扩张性降低。这些心血管变化还与肾素-血管紧张素（Ang）系统（RAS）活性降低和胰岛素抵抗有关。项目 4 的首要目标是确定胰岛素和 RAS 的特定成分如何共同作用，作为改变心血管调节的主要因素，最终导致衰老过程中收缩压升高以及高胰岛素血症和高血糖的加剧。我们专注于对手 Ang II 和 Ang-(1-7) 在孤束核 (nTS) 中的作用，调节交感神经和副交感神经流出的压力感受器反射控制。这些研究将确定胰岛素如何通过延髓和下丘脑心血管相关区域的作用，在自主神经流出的神经调节中与这两种肽协同或对抗。我们的实验策略将利用该项目成员的综合专业知识来定义神经系统、肽受体途径和相互作用的代谢成分，以解释心血管调节的改变 老化期间。具体目标 1 研究了以下假设：内源性 Ang-(1-7) 促进压力感受器反射功能的作用随着年龄的增长而减弱，因此 Ang II 和胰岛素的作用不受对抗，从而有助于减少心脏迷走神经流出，增强交感神经流出和高血压。实验将重点关注 nTS、下丘脑室旁核和延髓头端腹外侧核，这些部位是大脑中血管紧张肽和胰岛素在衰老过程中发生变化的关键部位。作为在衰老过程中导致 Ang 肽和胰岛素作用改变的一种机制，Specific Aim 2 将检验以下假设：脑组织中的 Ang-(1-7) 随着年龄的增长而减少，从而导致 Ang II 和 Ang II 的功能或表达发生变化。胰岛素。由于受体是细胞内的关键功能成分 前面提到的衰老过程中心血管功能的中枢调节，Specific Aim 3 将评估 Ang II 和 Ang-(1-7) 受体经历动态调节的假设，部分取决于这两种肽的组织水平的变化。特别是，所提出的实验将建立 AT1b 受体和 mas 孤儿受体之间发展的功能相互作用，作为响应 Ang-(1-7) 的关键元件。所提出的实验利用了脑血管紧张素原（ASrAogen）产生缺陷的转基因大鼠模型，我们证明该模型在通常与斯普拉格-道利大鼠衰老相关的同一时间范围内不会表现出心血管损伤。