Angiotensin-(1-7) and beta adrenergic receptor signaling in aging

衰老过程中血管紧张素 (1-7) 和 β 肾上腺素受体信号传导

• 批准号: 10448574
• 负责人: Amanda Joy Miller
• 金额: $ 10.6万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448574
• 关键词: Acute; Adrenergic Agents; Aging; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Animal Experimentation; Animals; Area; Attenuated; Blood Pressure; Blood Vessels; Cardiac; Cardiovascular Diseases; Cardiovascular Models; Cardiovascular Physiology; Cardiovascular system; Catecholamines; Cells; Chronic; Clinical; Clinical Research; Cross-Over Studies; Data; Development; Double-Blind Method; Endothelial Cells; Endothelium; Exhibits; Future; Gene Expression; Genes; Heart Rate; Hormones; Human; Hypertension; In Vitro; Infusion procedures; Intravenous; Knowledge; Laboratories; Link; Mentors; Mentorship; Mesenteric Arteries; Mesentery; Methods; Modeling; Molecular; Molecular Biology; Mus; Muscle; Nerve; Nitric Oxide; Nitric Oxide Signaling Pathway; Obesity; Participant; Pathway interactions; Phase; Placebo Control; Plasma; Production; Randomized; Receptor Signaling; Regulation; Renin-Angiotensin System; Research; Research Training; Risk Factors; Signal Transduction; Site; Smooth Muscle Myocytes; Sympathetic Nervous System; Techniques; Testing; Training; Translating; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; Work; age related; angiotensin I (1-7); antagonist; base; beta-2 Adrenergic Receptors; beta-adrenergic receptor; blood pressure elevation; blood pressure reduction; blood pressure variability; cardioprotection; cardiovascular risk factor; hypertensive; imaging modality; improved; in vivo; juvenile animal; molecular imaging; mouse model; new therapeutic target; novel; pre-clinical; prevent; programs; restoration; skills; transcriptome sequencing; translational potential

PROJECT SUMMARY Aging is an independent risk factor for developing hypertension and cardiovascular disease. An important hallmark of aging is increased sympathetic nervous system activity, which can decrease vascular β2 adrenergic receptors (β2AR) to reduce nitric oxide (NO)-dependent vasodilation and increase blood pressure. Accumulating evidence from our laboratory suggests that deficiency of angiotensin (Ang)-(1-7), a protective hormone of the renin-angiotensin system, provides an important link to connect aging with sympathetic overactivation and hypertension. In support of this, we have shown that aging mice exhibit circulating Ang-(1-7) deficiency, and chronic restoration of Ang-(1-7) lowers cardiac and vascular sympathetic tone and blood pressure in this model. Our preliminary data translate these findings to show that circulating Ang-(1-7) levels are similarly reduced in older healthy humans, with acute Ang-(1-7) restoration tending to decrease cardiac sympathetic tone and blood pressure and increase endothelial-dependent vasodilation. Importantly, our preliminary data provide evidence that cardioprotective effects of Ang-(1-7) in aging require activation of β2AR- signaling. We show that chronic Ang-(1-7) treatment selectively increases β2AR gene expression in mesenteric vessels from aging mice, and depressor effects of Ang-(1-7) are prevented by β2AR antagonism. Based on these data, this proposal will test the central hypothesis that Ang-(1-7) reduces sympathetic outflow to restore vascular β2AR-NO signaling and lower blood pressure in aging. Aim 1 will determine if acute Ang-(1- 7) infusion decreases sympathetic tone in older healthy humans, and if these effects are associated with increased endothelial-dependent vasodilation and reduced blood pressure. Aim 2 will determine if in vivo Ang- (1-7) treatment increases β2AR-NO signaling pathways in mesenteric arteries from aging mice and endothelial cells from older healthy humans. We will determine potential cellular mechanisms by which Ang-(1-7) interacts with adrenergic-vascular signaling in aging using RNA sequencing to guide future studies. Aim 3 will determine the vascular cell-specific site of action for depressor effects of Ang-(1-7) using genetically modified mouse models with deletion of β2AR in endothelial versus vascular smooth muscle cells. Aim 4 will determine if therapies blocking Ang II activity reduce sympathetic tone and blood pressure by activating endogenous Ang- (1-7) pathways. Overall, this proposal will capitalize on in vivo and in vitro techniques spanning the cellular to preclinical to clinical levels to determine the functional importance of adrenergic-vascular mechanisms to Ang- (1-7) cardiovascular actions in aging. These studies also have the potential to inform on whether Ang-(1-7) represents a novel therapeutic target for age-related cardiovascular disease. These studies logically build upon the PI’s translational background in integrative animal and clinical methods to assess cardiovascular autonomic regulation, will allow her to develop a new skillset in advanced molecular biology methods, and will provide strong mentorship and a research framework to establish an independent and novel area of research.

项目总结 老龄化是患高血压和心血管疾病的独立危险因素。一个重要的 衰老的标志是交感神经系统活动增加，这会减少血管β2 肾上腺素能受体(β2AR)可降低一氧化氮(NO)依赖的血管扩张和血压。 我们实验室的越来越多的证据表明，血管紧张素(Ang)-(1-7)的缺乏是一种保护性的 肾素-血管紧张素系统的激素，提供了联系衰老和交感神经的重要纽带 过度运动和高血压。为了支持这一点，我们已经表明，衰老的小鼠表现出循环Ang-(1-7) Ang-(1-7)缺乏和慢性恢复会降低心脏和血管交感神经张力和血液 这个模型中的压力。我们的初步数据将这些发现转化为循环Ang-(1-7)水平 在老年健康人中类似地减少，急性Ang-(1-7)修复倾向于减少心脏 交感神经张力和血压，并增加内皮依赖的血管扩张。重要的是，我们的 初步数据表明，血管紧张素-(1-7)在衰老过程中的心脏保护作用需要激活β-2AR- 发信号。我们发现慢性血管紧张素-(1-7)治疗选择性增加β-2AR基因的表达。 β-2AR拮抗Ang-(1-7)的降压作用可阻断衰老小鼠的肠系膜血管。 基于这些数据，这一提议将检验Ang-(1-7)减少交感神经流出的中心假设 恢复血管β2AR-NO信号通路，降低衰老血压。目标1将确定急性Ang-(1- 7)输液降低了老年健康人的交感神经张力，如果这些影响与 增加内皮依赖性血管扩张和降低血压。目标2将确定是否在体内和- (1-7)治疗增加衰老小鼠肠系膜动脉和血管内皮细胞的β2AR-NO信号通路 来自年长的健康人类的细胞。我们将确定Ang-(1-7)相互作用的潜在细胞机制 使用RNA测序来指导未来的研究。目标3将决定 血管紧张素-(1-7)对转基因小鼠降压作用的血管细胞特异性作用部位 血管内皮细胞β-2AR缺失的模型。目标4将决定是否 阻断血管紧张素II活性的治疗通过激活内源性血管紧张素转换酶降低交感神经张力和血压 (1-7)路径。总体而言，这项提议将利用体内和体外技术，跨越细胞到 临床前到临床水平，以确定肾上腺素能血管机制对血管紧张素转换酶的功能重要性。 (1-7)衰老过程中的心血管活动。这些研究也有可能告知Ang-(1-7) 代表了与年龄相关的心血管疾病的新治疗靶点。这些研究在逻辑上建立在 PI在动物和临床相结合的心血管评估方法中的翻译背景 自主调节，将使她在先进的分子生物学方法方面发展新的技能，并将 提供强有力的指导和研究框架，以建立一个独立和新颖的研究领域。