Oxidant stress and diabetic endothelial dysfunction

氧化应激与糖尿病内皮功能障碍

• 批准号: 7899404
• 负责人: MING-HUI ZOU
• 金额: $ 36.63万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 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/7899404
• 关键词: 26S proteasome; 3-nitrotyrosine; 5' -AMP-activated protein 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; progesterone 11-hemisuccinate-(2-iodohistamine); promoter; public health relevance; research study; sensor; tempol

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）：我们已发表的数据和本申请中提供的初步数据表明，高血糖症抑制AMPK，进而使糖尿病中的氧化应激和血管损伤持续存在。本申请的中心假设是AMPK 12抑制增加26 S活性，从而增加I：B1降解、p65核定位以及随后的NF：B激活。激活的NF：B与NOX 4、gp 91 phox（NOX 2）、p67 phox、p47 phox等NAD（P）H氧化酶亚基的启动子结合，导致NAD（P）H氧化酶活性和活性氧增加，导致内皮细胞功能障碍，加速动脉粥样硬化。26 S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氧化酶活化来预防内皮功能障碍和动脉粥样硬化形成。这一假设将在三个相互关联的目标进行检验。这前两个目的旨在确定慢性高血糖抑制AMPK是否起作用（目的#1）以及AMPK抑制是否引起糖尿病中粘附分子和氧化应激的异常表达（目的#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）。尽管动脉粥样硬化、氧化应激和AMPK在糖尿病中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。本文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发病机制中的作用的第一组确定性研究。因此，它们有可能解释在动物和糖尿病患者中发生的AMPK长期公认的减少。我们相信，拟议的研究将提供新的信息，如何与糖尿病相关的代谢应激导致内皮细胞损伤，内皮细胞如何试图保护自己免受这些压力，以及ONOO-或AMPK是否是潜在的治疗目标。 公共卫生关系：来自申请人小组和其他人的最近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）的常见致病机制的观点。但机制定义不清。因此，本申请旨在确定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;和3）确定AMPK抑制在体内动脉粥样硬化小鼠模型中糖尿病增强的动脉粥样硬化中的贡献。