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

基本信息

批准号：
10409555
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-15 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10409555
关键词：
Adhesions Adrenal Glands Adrenergic Receptor Affect Biological Assay Blood Blood flow Cardiovascular Diseases Cardiovascular Manifestation Carotid Body Catecholamines Cell Adhesion Molecules Cell Culture Techniques 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 Maintenance Measures Mediating Modeling Monitor Mus Norepinephrine Pathologic Pathway interactions Patients Persons Pharmacology 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 base beta-2 Adrenergic Receptors cardiovascular risk factor cytokine experience hypoxia inducible factor 1 in vivo indexing mRNA Expression macrophage member protein expression

项目摘要

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.

项目总结 - 项目 3 患有睡眠呼吸暂停 (SA) 的患者和暴露于间歇性缺氧 (IH)（SA 的一个标志）的啮齿类动物表现出内皮细胞（EC）激活，这是心血管疾病发展的早期病理事件当被激活时，ECs 表达的促炎细胞因子和细胞粘附水平增加。导致白细胞粘附到 EC 的分子项目 3 的总体目标是确定其机制。我们对暴露于 IH 的小鼠和主动脉 EC 的初步数据表明，SA/IH 引起了潜在的 EC 激活。 SA/IH 诱导的 EC 激活不是由 IH 直接引起的，而是由 IH 诱导的交感神经引起的此外，我们发现用激活衍生的肾上腺素（不是去甲肾上腺素）治疗EC。肾上腺素激活缺氧诱导因子（HIF）-1，并增加糖酵解，这两者我们最近根据初步数据，项目3将发现在异常血流情况下需要EC激活。检验 SA/IH 通过交感神经激活衍生的肾上腺素间接引起 EC 激活的假设，它通过 β2-肾上腺素能受体激活 HIF-1α，导致糖酵解上调，这是必需的我们将在两个 SA/IH 模型中测试我们的三个特定目标的假设：（1）实验 IH 和 (2) 自发性 SA 小鼠的暴露在目标 1 中，我们将确定交感神经激活是否- 衍生的肾上腺素介导 IH 诱导的 EC 激活和巨噬细胞粘附。在目标 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。在目标 3 中，我们将确定是否需要。 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 IH 诱导的肾上腺素激活 HIF-1 的机制在目标 4 中，我们将确定是否存在。 HIF-1 增加的糖酵解是 IH 诱导的 EC 激活所必需的，项目 3 与主题紧密相关。项目 1、2 和 4 并利用核心 B 设施：a) 将小鼠暴露于 IH，b) 维持和基因分型基因工程小鼠；c) 研究小组成员进行了定量实时 PCR 分析。对拟议方法的长期经验和专业知识以及出色的工作记录联合出版物证明了合作多年。拟议的研究将提供一个框架。了解 CIH 诱导的交感神经激活在引起 EC 炎症中的具体作用。拟议的研究将使我们能够确定肾上腺素/β2-肾上腺素能受体信号传导是否可以旨在减轻 SA/IH 诱导的 EC 激活以及由此产生的心血管疾病。