Mechanisms Underlying Sympathetic Activation-dependent Endothelial Cell Activation by Chronic Intermittent Hypoxia

慢性间歇性缺氧导致交感神经激活依赖性内皮细胞激活的机制

• 批准号: 10612099
• 负责人: Gokhan M. Mutlu
• 金额: $ 38.07万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612099
• 关键词: Ablation; Adhesions; Adrenal Glands; Affect; Aorta; Biological Assay; Blood; Blood flow; Cardiovascular Diseases; Cardiovascular Manifestation; Carotid Body; Catecholamines; Cell Adhesion Molecules; Cell Culture Techniques; Cell Separation; Cellular Metabolic Process; Chronic; Cyclic AMP-Dependent Protein Kinases; Data; Development; Endothelial Cells; Enzymes; Epinephrine; Event; Exhibits; Exposure to; Genetic Transcription; Genetically Engineered Mouse; Genotype; Genus Hippocampus; Glycolysis; Goals; Hexokinase 2; Human; Hypoxia; Hypoxia Inducible Factor; In Vitro; Inflammation; Inflammatory; Joints; Leukocytes; Macrophage; Maintenance; Measures; Mediating; Modeling; Monitor; Mus; Norepinephrine; Pathologic; Pathway interactions; Patients; Persons; Plasma; Play; Preventive measure; Publications; Receptor Signaling; Reflex action; Respiratory Disease; Rodent; Role; Sleep Apnea Syndromes; Testing; Time; Transcription Coactivator; Up-Regulation; Vascular Endothelial Cell; beta-2 Adrenergic Receptors; cardiovascular risk factor; cytokine; experience; hypoxia inducible factor 1; in vivo; indexing; mRNA Expression; member; pharmacologic; protein expression

Project Summary- Project 3 Patients with sleep apnea (SA) and rodents exposed to intermittent hypoxia (IH), a hallmark of SA, exhibit endothelial cell (EC) activation, which is an early pathologic event in the development of cardiovascular disease. When activated, ECs express increased levels of pro-inflammatory cytokines and cell adhesion molecules leading to leukocyte adhesion to EC. The overall goal of Project 3 is to determine the mechanisms underlying EC activation caused by SA/IH. Our preliminary data from IH-exposed mice and aortic ECs suggest that SA/IH-induced EC activation is not caused directly by IH but secondarily by IH-induced sympathetic activation-derived epinephrine (not by norepinephrine). Furthermore, we found that treating ECs with epinephrine activates hypoxia-inducible factor (HIF)-1, and increases glycolysis, both of which we recently found to be required for EC activation under abnormal blood flow. Based on the preliminary data, Project 3 will test the hypothesis that SA/IH causes EC activation indirectly via sympathetic activation-derived epinephrine, which through β2-adrenergic receptors activates HIF-1α leading to upregulation of glycolysis, which is required for EC activation. We will test our hypothesis in three specific aims in two models of SA/IH: (1) experimental exposure of IH and (2) mice with spontaneous SA. In Aim 1, we will determine whether sympathetic activation- derived epinephrine mediates IH-induced EC activation and macrophage adhesion. In Aim 2, we will determine whether β2-adrenergic receptors are required for IH-induced EC activation. In Aim 3, we will determine whether IH-induced epinephrine causes EC activation through HIF-1-dependent manner and further assess the mechanism(s) by which HIF-1 is activated by IH-induced epinephrine. In Aim 4, we will determine whether increased glycolysis by HIF-1 is required for IH-induced EC activation. Project 3 has tight thematic linkages to Projects 1, 2, and 4 and utilizes Core B facilities for: a) exposing mice to IH, b) maintenance and genotyping of genetically engineered mice; c) quantitative real-time-PCR analysis. Members of the investigative team have long-standing experience and expertise with the proposed approaches and excellent track record of working together for number of years as evidenced by joint publications. The proposed studies will provide a framework for understanding the specific role of CIH-induced sympathetic activation in causing EC inflammation. Findings from the proposed studies will allow us to determine whether epinephrine/β2-adrenergic receptor signaling can be targeted to alleviate SA/IH-induced EC activation and the resulting cardiovascular disease.

项目摘要 - 项目3 SA的标志，患有间歇性缺氧（IH）的睡眠呼吸暂停（SA）和啮齿动物的患者 内皮细胞（EC）激活，这是心血管发展的早期病理事件 疾病。激活后，EC表达促炎性细胞因子和细胞粘附水平的升高 导致白细胞粘附于EC的分子。项目3的总体目标是确定机制 SA/IH引起的基础EC激活。我们来自IH暴露的小鼠和主动脉EC的初步数据建议 SA/IH诱导的EC激活不是直接由IH引起的，而是由IH引起的同情 激活衍生的肾上腺素（不通过去甲肾上腺素）。此外，我们发现用 肾上腺素激活缺氧诱导因子（HIF）-1，并增加糖酵解，我们最近两者都 发现在异常血流下EC激活所必需。根据初步数据，项目3将 检验SA/IH通过交感激活肾上腺素间接引起EC激活的假设， 通过β2-肾上腺素受体激活HIF-1α导致糖酵解的上调，这是必需的 用于EC激活。我们将在SA/IH的两种模型中以三个特定目的测试我们的假设：（1）实验 带有赞助SA的IH和（2）小鼠的暴露。在AIM 1中，我们将确定是否同情激活 - 衍生的肾上腺素介导IH诱导的EC激活和巨噬细胞粘合剂。在AIM 2中，我们将确定 IH诱导的EC激活是否需要β2-肾上腺素受体。在AIM 3中，我们将确定是否 IH诱导的肾上腺素通过HIF-1依赖性方式引起EC激活，并进一步评估 通过IH诱导的肾上腺素激活HIF-1的机制。在AIM 4中，我们将确定是否 IH诱导的EC激活需要HIF-1糖酵解增加。项目3具有紧密的主题联系 项目1、2和4，并利用核心B设施：a）将老鼠暴露于IH，b）维护和基因分型 一般设计的小鼠； c）定量实时PCR分析。调查团队的成员有 长期以来的经验和专家在拟议的方法和工作方面的出色记录 共同出版物所证明的是多年。拟议的研究将提供一个框架 了解CIH引起的交感神经激活在引起EC炎症中的特定作用。发现 根据拟议的研究，我们可以确定肾上腺素/β2-肾上腺素能受体信号是否可以 旨在减轻SA/IH诱导的EC激活和由此产生的心血管疾病。