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HDAC1 Regulation of Endothelial NO

HDAC1 对内皮 NO 的调节

基本信息

批准号：
10245088
负责人：
Luke Stewart Dunaway
金额：
$ 1.4万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
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：
2019-09-01 至 2021-12-22
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10245088
关键词：
Acetylation Arginine Biological Availability Cardiovascular Diseases Cardiovascular system Cell physiology Cessation of life Complex Data Deacetylation Dependence Endothelial Cells Endothelium Enzymes Epigenetic Process Family Fellowship Foundations Future Genes Genetic Transcription Glutamine Goals HDAC1 gene Health Healthcare Histone Deacetylase Histones Human Impairment Injury Intake Juxtamedullary Nephron Kidney Knock-out Knockout Mice Knowledge Learning Lysine Mediating Modification Mus Mutation NADPH Oxidase NOS3 gene Nitric Oxide Nitric Oxide Synthase Nuclear Oxidative Stress Post-Translational Protein Processing Preparation Production Protein Isoforms Proteins Publications Rattus Reactive Oxygen Species Regulation Renal function Research Personnel Risk Role Signal Transduction Site Sodium Sodium Chloride Sprague-Dawley Rats Techniques Testing Vascular Endothelium cardiovascular disorder therapy career cell type high salt diet histone modification in vivo insight kidney vascular structure mortality new therapeutic target non-histone protein novel novel therapeutics overexpression promoter renal artery renal damage salt intake

项目摘要

PROJECT SUMMARY Excess sodium intake accounts for billions of healthcare dollars every year. In 2010, 1.65 million deaths from cardiovascular disease were attributed to a high salt diet. Furthermore, sodium intake directly correlates with kidney function and mortality. A high salt diet causes cardiovascular and renal damage by increasing oxidative stress and impairing endothelial nitric oxide (NO) signaling. The mechanisms by which a high salt diet leads to NOS3 uncoupling and increased NADPH oxidase 2 (Nox2) expression and activity remains elusive. NOS3 uncoupling is characterized by an increase in NOS-dependent reactive oxygen species (ROS) and a decrease in NOS-dependent NO. The central hypothesis to the proposed studies is that high salt increases endothelial HDAC1 which uncouples NOS3 via post-translational modification (deacetylation) and increases Nox2 expression and activity via a transcriptional mechanism. In order to study the role of HDAC1 in NOS3 uncoupling, intra-renal arteries and renal endothelial cells will be isolated from normal and high salt fed rats. HDAC1 activity as well as HDAC1 dependence of NOS3 uncoupling and NOS3 acetylation will be assessed. We will generate vascular endothelial HDAC1 knockout (VEHDAC1KO) mice to investigate the necessity of HDAC1 in high salt disrupted NO signaling. The juxtamedullary nephron preparation will be used to assess NO signalling in small intra-renal arteries. In order to identify which NOS3 lysines are susceptible to HDAC1 deacetylation, we will utilize NOS3 constructs containing specific lysine (K) to arginine (R) or glutamine (Q) mutations. Cdh5- CreERT2-Nox2KO mice will be used to assess the role of endothelial Nox2 in high salt disrupted NO signaling in small intra-renal arteries. We will use VEHDAC1KO mice to elucidate the role of HDAC1 in high salt increased Nox2 complex expression. ChIP-qPCR will be utilized to assess the effect of HDAC1 on histone modifications at the promoters of the genes of the Nox2 complex. The long-term goal of this project is to understand the role of HDAC1 in endothelial NO signaling in order to develop novel therapies for cardiovascular disease.

项目摘要过量的钠摄入每年占数十亿美元的医疗保健费用。2010年，导致心血管疾病的原因是高盐饮食。此外，钠的摄入量与与肾功能和死亡率有关。高盐饮食会增加心血管和肾脏的损害，氧化应激和损害内皮一氧化氮（NO）信号传导。高盐饮食的机制导致NOS 3解偶联和NADPH氧化酶2（Nox 2）表达和活性增加仍然是难以捉摸的。 NOS 3解偶联的特征在于NOS依赖性活性氧（ROS）的增加，所提出的研究的中心假设是，高盐会增加内皮HDAC 1通过翻译后修饰（脱乙酰化）解偶联NOS 3，通过转录机制的Nox 2表达和活性。为了研究HDAC 1在NOS 3中的作用，解偶联、肾内动脉和肾内皮细胞将从正常和高盐喂养的大鼠中分离。将评估HDAC 1活性以及NOS 3解偶联和NOS 3乙酰化的HDAC 1依赖性。我们将产生血管内皮HDAC 1敲除（VEHDAC 1 KO）小鼠，以研究HDAC 1的必要性。高盐破坏NO信号传导。将使用髓质肾单位制备物评估NO信号传导肾内小动脉为了鉴定哪些NOS 3赖氨酸对HDAC 1脱乙酰化敏感，我们将利用含有特异性赖氨酸（K）至精氨酸（R）或谷氨酰胺（Q）突变的NOS 3构建体。Cdh 5- CreERT 2-Nox 2KO小鼠将用于评估内皮Nox 2在高盐破坏的NO信号传导中的作用肾内小动脉我们将使用VEHDAC 1 KO小鼠来阐明HDAC 1在高盐增加中的作用。 Nox 2复合物表达。ChIP-qPCR将用于评估HDAC 1对组蛋白修饰的影响， Nox 2复合体基因的启动子。该项目的长期目标是了解 HDAC 1在内皮NO信号转导中的作用，以开发心血管疾病的新疗法。