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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：
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
项目类别：
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

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.

项目摘要-项目3