Oxidant stress and diabetic endothelial dysfunction

氧化应激与糖尿病内皮功能障碍

基本信息

批准号：
8228189
负责人：
MING-HUI ZOU
金额：
$ 36.26万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8228189
关键词：
26S proteasome 3-nitrotyrosine 5&apos -AMP-activated protein kinase AMP-activated protein kinase kinase Abbreviations Affect Animals Antioxidants Aorta Atherosclerosis Binding Blood Vessels Cardiovascular Diseases Cell Adhesion Molecules Cell Nucleus Cells Chemicals Chronic Complex Coupled Data Development Diabetes Mellitus Diabetic mouse Dominant-Negative Mutation Endothelial Cells Endothelium Free Radicals Functional disorder Genetic Glucose Goals Health Human Hydrogen Peroxide Hyperglycemia Hypertension Inflammation Injury Ischemic Preconditioning Knock-out Knockout Mice Lesion Link Low Density Lipoprotein Receptor MG132 Mass Spectrum Analysis Mediating Metabolic stress Metformin Modification Molecular Mus NG-Nitroarginine Methyl Ester Nitric Oxide Nonesterified Fatty Acids Nuclear Translocation Oxidants Oxidases Oxidation-Reduction Oxidative Stress Pathogenesis Patients Peptide Mapping Peroxonitrite Polyethylene Glycols Production Prostacyclin synthase Prostaglandins Proteasome Inhibition Proteasome Inhibitor Protein Kinase C Proteins Publishing Reaction Reactive Nitrogen Species Reactive Oxygen Species Recombinants Resistance Role Small Interfering RNA Streptozocin Stress Superoxide Dismutase Superoxides TNFRSF5 gene Testing Transactivation Transgenic Mice Tyrosine UCP2 protein Uric Acid activity marker arginine methyl ester atherogenesis clinically relevant design diabetic human NOS3 protein in vivo insight mouse model multicatalytic endopeptidase complex mutant neutrophil cytosol factor 67K nitration novel overexpression oxidant stress p65 polyethylene glycol-superoxide dismutase prevent promoter research study sensor tempol

项目摘要

DESCRIPTION (provided by applicant): Our published data and the preliminary data presented in this application have demonstrated that hyperglycemia suppresses AMPK, which in turn perpetuates oxidative stress and vascular injury in diabetes. The central hypothesis of this application is that AMPK12 inhibition increases 26S activity, which increases I:B1 degradation, p65 nucleus localization, and consequent NF:B activation. Activated NF:B binds to the promoter of NAD(P)H oxidase subunits, including NOX4, gp91phox(NOX2), p67phox, p47phox, resulting in an increase in NAD(P)H oxidase activity and ROS, which causes endothelial cell dysfunction and accelerated atherosclerosis. Chronic proteasome inhibition of the 26S proteasome prevents endothelial dysfunction and atherogenesis by inhibiting proteasome-dependent NF:B-mediated activation of NAD(P)H oxidase. This hypothesis will be tested in three interrelated aims. These first two aims are designed to establish whether chronic hyperglycemia inhibition AMPK functions (Aim #1) and whether AMPK inhibition causes abnormal expression of adhesion molecules and oxidant stress in diabetes (Aim #2). Finally, we will test the contributions of RNS-mediated AMPK inhibition in the development of accelerated atherosclerosis in diabetes (Aim #3). Although the in vivo relationships among atherosclerosis, oxidant stress, and AMPK in diabetes are undoubtedly complex, the emerging role for AMPK in oxidant stress and atherosclerosis warrant further study. The studies proposed here represent the first set of definitive studies to determine the role of ONOO- and AMPK inhibition in the pathogenesis of diabetic vascular dysfunction and atherosclerosis. As such, they have the potential to explain the long recognized decrease in AMPK that occurs in animals and human patients with diabetes. We believe that the proposed studies will provide novel information as to how the metabolic stress associated with diabetes causes damage to the endothelium and how the endothelial cell attempts to protect itself against these stresses and whether ONOO- or AMPK are potential targets for therapy. PUBLIC HEALTH RELEVANCE: Recent studies from the applicant's group and others support the idea that oxidant stress is a common pathogenic mechanism for cardiovascular diseases including diabetes, hypertension, and atherosclerosis. But the mechanisms are poorly defined. Thus, this application is aimed to determine 1) how diabetes inhibits AMPK in endothelial cells; 2) To determine how AMPK inhibition results in excessive inflammation and oxidant stress; and 3) to determine the contribution of AMPK inhibition in diabetes-enhanced atherosclerosis in mouse models of atherosclerosis in vivo.

描述（由申请人提供）：我们已发布的数据和本申请中介绍的初步数据表明，高血糖抑制AMPK，这反过来又抑制了糖尿病中氧化应激和血管损伤。该应用的中心假设是AMPK12抑制增加了26S活性，这增加了I：B1降解，P65核定位以及随之而来的NF：B激活。活化的NF：B与NAD（P）H氧化酶亚基的启动子结合，包括NOX4，GP91Phox（NOX2），P67Phox，P47Phox，导致NAD（P）H氧化酶活性和ROS的增加，这会导致内皮细胞功能障碍和加速效果。慢性蛋白酶体对26S蛋白酶体的抑制可通过抑制蛋白酶体依赖性NF：B介导的NAD（P）H氧化酶的激活来阻止内皮功能障碍和动脉粥样硬化。该假设将以三个相互关联的目的进行检验。这两个目标旨在确定慢性高血糖抑制AMPK功能（AIM＃1）以及AMPK抑制是否会导致糖尿病中粘附分子和氧化应激的异常表达（AIM＃2）。最后，我们将测试RNS介导的AMPK抑制在糖尿病加速动脉粥样硬化发展中的贡献（AIM＃3）。尽管糖尿病动脉粥样硬化，氧化剂应激和AMPK之间的体内关系无疑是复杂的，但AMPK在氧化应激和动脉粥样硬化中的新兴作用需要进一步研究。此处提出的研究代表了确定ONOO和AMPK抑制在糖尿病血管功能障碍和动脉粥样硬化的发病机理中的作用的第一组确定研究。因此，它们有可能解释动物和人类糖尿病患者的AMPK的长期识别降低。我们认为，拟议的研究将提供有关与糖尿病相关的代谢应激如何损害内皮以及内皮细胞如何试图保护自己免受这些胁迫以及ONOOO-或AMPK是治疗的潜在靶标。公共卫生相关性：申请人小组和其他人的最新研究支持氧化应激是心血管疾病（包括糖尿病，高血压和动脉粥样硬化）的常见致病机制。但是这些机制的定义很差。因此，该应用的目的是确定1）糖尿病如何抑制内皮细胞中的AMPK； 2）确定AMPK抑制如何导致过度炎症和氧化应激； 3）确定在体内动脉粥样硬化的小鼠模型中，AMPK抑制在糖尿病增强的动脉粥样硬化中的贡献。