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HDAC1 Regulation of Endothelial NO

HDAC1 对内皮 NO 的调节

基本信息

批准号：
10020771
负责人：
Luke Stewart Dunaway
金额：
$ 3.88万
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10020771
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.

项目总结