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: 10629280
• 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/10629280
• 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; Soluble Guanylate Cyclase; Sympathetic Nervous System; Techniques; Testing; Training; Translating; Vascular Endothelium; Vascular Smooth Muscle; Vasodilation; Work; age related; angiotensin I (1-7); antagonist; 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; receptor expression; 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.

项目概要 衰老是发生高血压和心血管疾病的一个重要的独立危险因素。 衰老的标志是交感神经系统活动增加，这会降低血管β2 肾上腺素能受体（β2AR）可减少一氧化氮（NO）依赖性血管舒张并增加血压。 我们实验室积累的证据表明，缺乏血管紧张素 (Ang)-(1-7)（一种保护性血管紧张素） 肾素-血管紧张素系统的激素，提供了将衰老与交感神经联系起来的重要联系 为了支持这一点，我们已经证明衰老小鼠表现出循环 Ang-(1-7)。 Ang-(1-7) 缺乏和长期恢复会降低心脏和血管交感神经张力和血液 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，Ang-(1-7) 的急性恢复往往会降低心脏 重要的是，我们的交感神经张力和血压增加，并增加内皮依赖性血管舒张。 初步数据证明，Ang-(1-7) 在衰老过程中的心脏保护作用需要激活 β2AR- 我们发现长期 Ang-(1-7) 治疗选择性增加 β2AR 基因表达。 β2AR 拮抗作用可防止衰老小鼠的肠系膜血管和 Ang-(1-7) 的抑制作用。 基于这些数据，该提案将检验 Ang-(1-7) 减少交感神经流出的中心假设 恢复血管 β2AR-NO 信号传导并降低衰老过程中的血压 目标 1 将确定是否存在急性 Ang-(1-)。 7) 输注会降低老年健康人的交感神经张力，如果这些影响与 目标 2 增加内皮依赖性血管舒张和降低血压将决定体内 Ang- 是否有效。 (1-7) 治疗增加衰老小鼠肠系膜动脉和内皮细胞中的 β2AR-NO 信号通路 我们将确定 Ang-(1-7) 相互作用的潜在细胞机制。 目标 3 将确定使用 RNA 测序指导衰老过程中的肾上腺素血管信号传导。 使用转基因小鼠研究 Ang-(1-7) 抑制作用的血管细胞特异性作用位点 内皮细胞与血管平滑肌细胞中 β2AR 缺失的模型将确定是否有效。 阻断 Ang II 活性的疗法通过激活内源性 Ang-II 降低交感神经张力和血压 (1-7) 途径总体而言，该提案将利用跨越细胞的体内和体外技术。 临床前到临床水平以确定肾上腺素血管机制对血管紧张素的功能重要性 (1-7) 衰老过程中的心血管作用 这些研究还有可能揭示 Ang-(1-7) 是否具有作用。 这些研究逻辑上代表了与年龄相关的心血管疾病的新治疗靶点。 PI 在评估心血管疾病的综合动物和临床方法方面的转化背景 自主调节，将使她能够开发先进分子生物学方法的新技能，并将 提供强有力的指导和研究框架，以建立独立且新颖的研究领域。