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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：
7219424
负责人：
MING-HUI ZOU
金额：
$ 34.73万
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 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7219424
关键词：
1,2-diacylglycerol 1-Phosphatidylinositol 3-Kinase 3-nitrotyrosine Abbreviations Adhesions Affect Apoptosis Biological Blood Vessels Bos taurus Cattle Cell Adhesion Molecules Cells Ceramides Development Diabetes Mellitus Diabetic Angiopathies Diglycerides Elevation End Point Endothelial Cells Endothelium Epoprostenol Free Radicals Functional disorder GLUT4 gene Generations Glucose Glucose Transporter Human Hyperglycemia Hyperlipidemia Insulin Insulin Receptor Insulin Resistance Knockout Mice Link Metabolic stress Molecular Morbidity - disease rate NG-Nitroarginine Methyl Ester National Research Service Awards Nitrates Nitric Oxide Nonesterified Fatty Acids Numbers Oxidants Oxidative Stress Oxygen PTGS2 gene Patients Peroxonitrite Phosphatidylinositols Phosphorylation Physiological Plasma Polyethylene Glycols Production Prostacyclin synthase Prostaglandin H2 Prostaglandin H2 Receptor Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Protein Kinase Protein Kinase C Proteins Proto-Oncogene Proteins c-akt Reaction Reactive Nitrogen Species Receptor Activation Resistance Role Signal Transduction Signaling Molecule Somatomedins Source Streptozocin Stress Superoxide Dismutase Superoxides Thromboxane A2 Thromboxane A2 Receptor Thromboxane Receptor Thromboxanes Transgenic Mice Tyrosine Vascular Diseases Vasoconstrictor Agents arginine methyl ester base cell injury clinically relevant cyclooxygenase 1 day diabetic exposed human population fatty acid oxidation glucose uptake human NOS3 protein insight insulin signaling mortality nitrate nitration novel polyethylene glycol-superoxide dismutase progesterone 11-hemisuccinate-(2-iodohistamine)von Willebrand Factor

项目摘要

DESCRIPTION (provided by applicant): Endothelial dysfunction represents a common pathogenic framework that contributes in both types of diabetes mellitus to the development of vascular disease that affects micro- and macro- blood vessels. Recent evidence indicates that the endothelial dysfunction associated with diabetes is the local formation of oxidants and free radicals. However, the mechanisms by which diabetes increases oxidant stress, and those by which oxidant stress modifies endothelial function are poorly understood. Our preliminary results have established new insights into how hyperglycemia and/or hyperlipidemia increase oxidant stress. Exposure of cultured human aortic endothelial cells to elevated glucose for 3-10 days increases the production of superoxide anion (O2), which reacts with nitric oxide (NO) to generate a potent oxidant, ONOO. Increased levels of its reaction product with tyrosine, 3-nitrotyrosine, are found in the cells. Although the function of many proteins may be affected, we have found that prostacyclin synthase (PGIS) is particularly susceptible to tyrosine nitration in human aortic endothelial cells exposed to elevated glucose. The levels of nitrated PGIS increase and its activity decreases. This may not only explain why diabetes decreases levels of PGI2, but also why increases have been noted in the PGI2 precursor, PGH2, which acts upon thromboxane A2 receptor (termed TP-receptor, TPr). Our preliminary studies have shown that exposure of human aortic endothelial cell to elevated glucose enhances adhesion molecular expression, endothelial cell apoptosis, inhibits Akt and insulin signaling by mechanisms which depend on ONOO- and TPr activation. Our central hypothesis is that diabetes via hyperglycemia/hyperlipidemia increases the generation of O2 and then ONOO, resulting in PGIS nitration and TPr stimulation and insulin resistance. The aims of the proposed studies are: 1). To determine the role(s) of ONOO-triggered PGIS nitration and TPr activation in enhancing endothelial cell adhesion molecule expression and apoptosis in the HAEC cells exposed to hyperglycemia/FFAs and to determine if PGIS is resistant to nitration caused by the streptozotocin-indued diabetes in the transgenic mice (hSOD +/+) or knockout mice (eNOS -/-, gp91phox-/-). 2). To establish the links between cellular oxidant stress, PGIS nitration and TPr activation, and impaired insulin signaling in cells exposed to hyperglycemia/FFAs. Based on the results, we will assess which of these alterations is likely to be pathogenetic for cell damage. These studies will provide novel information as to how the metabolic stress associated with diabetes cause damage to the endothelium and how endothelial cell attempts to protect itself against these stresses and whether ONOO or TPr are potential targets for therapy.

描述（由申请方提供）：内皮功能障碍代表了一种常见的致病框架，在两种类型的糖尿病中均会导致影响微血管和大血管的血管疾病的发展。最近的证据表明，与糖尿病相关的内皮功能障碍是氧化剂和自由基的局部形成。然而，糖尿病增加氧化应激和氧化应激改变内皮功能的机制知之甚少。我们的初步研究结果建立了新的见解如何高血糖症和/或高脂血症增加氧化应激。将培养的人主动脉内皮细胞暴露于升高的葡萄糖3-10天增加超氧阴离子（O2）的产生，超氧阴离子（O2）与一氧化氮（NO）反应以产生有效的氧化剂ONOO。在细胞中发现其与酪氨酸的反应产物3-硝基酪氨酸水平增加。虽然许多蛋白质的功能可能会受到影响，我们已经发现，前列环素合酶（PGIS）是特别容易受到酪氨酸硝化在人主动脉内皮细胞暴露于葡萄糖升高。硝化PGIS的水平增加，其活性降低。这不仅可以解释为什么糖尿病会降低PGI 2水平，而且还可以解释为什么PGI 2前体PGH 2会增加，PGH 2作用于血栓烷A2受体（称为TP受体，TPr）。我们的初步研究表明，高糖诱导的人主动脉内皮细胞粘附分子表达增强，内皮细胞凋亡，Akt和胰岛素信号通路受到抑制，其机制依赖于ONOO-和TPr的激活。我们的中心假设是，糖尿病通过高血糖/高脂血症增加O2的产生，然后ONOO，导致PGIS硝化和TPr刺激和胰岛素抵抗。本研究的目的是：1）。目的探讨ONOO诱导的PGIS硝化和TPr激活在高血糖/FFA诱导的HAEC内皮细胞粘附分子表达和凋亡中的作用，以及PGIS对链脲佐菌素（streptozotocin，STZ）诱导的糖尿病转基因小鼠（hSOD +/+）和eNOS-/-、gp 91 phox-/-小鼠（eNOS -/-、gp 91 phox-/-）硝化的抵抗作用。2）。建立细胞氧化应激、PGIS硝化和TPr激活与暴露于高血糖/FFA的细胞中受损的胰岛素信号传导之间的联系。根据结果，我们将评估这些改变中的哪一个可能是细胞损伤的致病因素。这些研究将提供新的信息，与糖尿病相关的代谢应激如何导致内皮损伤，内皮细胞如何试图保护自己免受这些应激，以及ONOO或TPr是否是潜在的治疗靶点。