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：
8432819
负责人：
MING-HUI ZOU
金额：
$ 34.52万
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 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432819
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 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 public health relevance 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.

描述（由申请人提供）：我们发表的数据和本申请中提供的初步数据表明，高血糖会抑制 AMPK，进而使糖尿病中的氧化应激和血管损伤永久化。该应用的中心假设是 AMPK12 抑制会增加 26S 活性，从而增加 I:B1 降解、p65 核定位以及随后的 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 增加，从而导致内皮细胞功能障碍和加速动脉粥样硬化。 26S 蛋白酶体的慢性蛋白酶体抑制通过抑制蛋白酶体依赖性 NF:B 介导的 NAD(P)H 氧化酶激活来防止内皮功能障碍和动脉粥样硬化形成。该假设将在三个相互关联的目标中得到检验。前两个目标旨在确定慢性高血糖抑制 AMPK 是否发挥作用（目标＃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（目标＃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作用（目标#3）。尽管糖尿病中动脉粥样硬化、氧化应激和 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作用值得进一步研究。这里提出的研究代表了第一组明确的研究，以确定 ONOO- 和 AMPK 抑制在糖尿病血管功能障碍和动脉粥样硬化发病机制中的作用。因此，它们有可能解释长期以来公认的动物和人类糖尿病患者中 AMPK 下降的现象。我们相信，拟议的研究将提供新的信息，说明与糖尿病相关的代谢应激如何对内皮细胞造成损害，内皮细胞如何试图保护自身免受这些应激，以及 ONOO- 或 AMPK 是否是潜在的治疗靶点。