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

衰老、压力反射和 Ang-(1-7) 受体

• 批准号: 7218011
• 负责人: Debra I Diz
• 金额: $ 19.48万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7218011
• 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.

衰老的特征是心血管调节的进行性损害，其中可能包括增加交感神经流出，迷走神经活动减少和血管扩张性降低。这些心血管变化也与肾素 - 血管紧张素（ANG）系统（RAS）和胰岛素抵抗的活性降低有关。项目4的整个目标是定义RAS的胰岛素和特定组成部分如何将心血管调节的主要因素融为一体，最终导致高胰岛素血症和高血糖的收缩压升高，并加剧了衰老过程。我们专注于对立 Ang II和Ang-（1-7）在孤立道（NTS）核中调节压力感受器反射对交感神经和副交感神经流出的控制。该研究将定义胰岛素如何通过在延髓和下丘脑的心血管相关区域的作用在自主流出的神经调节中与这两种肽进行作用。我们的实验策略将借鉴项目成员的综合专业知识来定义神经系统，肽受体途径和代谢成分，这些成分相互作用以说明心血管调节的修改 在衰老期间。具体目标1研究了内源性ANG-（1-7）在衰老中促进压力感受器反射功能的作用，使ANG II和胰岛素的作用降低，从而没有反应，从而有助于减少心脏流失，增强的交感神经流失和高血压。实验将集中于下丘脑的NTS，室室核和腹侧腹侧髓质，作为大脑中的关键部位，在衰老过程中，ANG肽和胰岛素的作用发生了变化。作为一种导致ANG肽和胰岛素在衰老特异性目标中的作用改变的机制，将检验以下假设：脑组织中的Ang-（1-7）随着年龄的增长而减小，从而导致ANG II和胰岛素的功能或表达变化。由于受体构成了关键功能成分 前面提到的心血管功能的中央调节在衰老期间，特定的目标3将评估Ang II和Ang-（1-7）受体经历动态调节的假设，部分由这两种肽的组织水平改变确定。特别是，提出的实验将建立AT1B受体和Mas Orphan受体之间发展的功能相互作用，作为对Ang-（1-7）响应的关键要素。提出的实验利用了缺乏脑血管紧张素原（Asraogen）产生的转基因大鼠模型，我们表明，在通常与Sprague-Dawley大鼠衰老相关的同一时间范围内，我们表明不会表现出心血管障碍。