Adiponectin Improves Vascular Function In High Glucose

脂联素改善高血糖情况下的血管功能

• 批准号: 6954663
• 负责人: BARRY J. GOLDSTEIN
• 金额: $ 35.1万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6954663
• 关键词: NAD(P)H dehydrogenase; adenosine monophosphate; biological signal transduction; blood proteins; cardiovascular function; cell adhesion molecules; cell cell interaction; enzyme activity; gene expression; genetically modified animals; hyperglycemia; insulin dependent diabetes mellitus; intravital microscopy; laboratory mouse; laboratory rat; nitric oxide; nitric oxide synthase; nuclear factor kappa beta; phosphorylation; protein kinase C; protein structure function; recombinant proteins; superoxides; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): Vascular disease is a major cause of morbidity and mortality in patients with Type 1 diabetes. Hyperglycemia causes endothelial dysfunction, a pathological state consisting of reduced nitric oxide (NO) bioavailability, increased cellular superoxide production and activation of an inflammatory cascade with increased expression of adhesion molecules at the endothelial cell surface, that leads to the initiation and progression of vascular disease in diabetes. In preliminary studies, we have found that adiponectin, an abundant circulating plasma protein, suppresses high glucose-induced endothelial superoxide generation and enhances NO production in vascular endothelial cells. We and others have also found that adiponectin activates AMP kinase in various cell types including endothelial cells. In this project, we will characterize the signaling mechanism(s) used by adiponectin to improve endothelial function under high glucose conditions. By studying endothelial cells in culture in vitro and mesenteric microvascular endothelial cells in situ by intravital microscopy, we will test the hypotheses that the globular domain of adiponectin (gAd) expressed in a bacterial system and the full-length adiponectin protein (fAd) expressed in a recombinant eukaryotic system: (1) suppress superoxide production by endothelial cells treated with high glucose, possibly via an NAD(P)H oxidase-linked pathway regulated by protein kinase C; (2) enhance NO production by endothelial cells treated with high glucose, possibly via an AMP kinase-linked pathway; and (3) ameliorate endothelial dysfunction in vivo in rodent models of hyperglycemia as evidenced by salutary effects on leukocyte-endothelial interactions, expression of cell adhesion molecules and NO production. The in vivo studies will also be facilitated by using adiponectin knock-out mice, available to us by a research collaboration, which should demonstrate augmented vascular effects of adiponectin when the various forms are administered on a background of no endogenous circulating adiponectin. This powerful combination of in vitro and in vivo techniques will provide insight into adiponectin signal transduction in endothelial cells and may lead to new targets to reduce the heightened vascular risk associated with type 1 diabetes.

描述（由申请人提供）： 血管疾病是1型糖尿病患者发病率和死亡率的主要原因。高血糖会导致内皮功能障碍，这是一种病理状态，由一氧化氮（NO）生物利用度降低，细胞超氧化物的产生增加以及炎症性级联反应的激活，并增加内皮细胞表面粘附分子的表达，从而导致射血症中透射蛋白疾病的起始和进展。在初步研究中，我们发现脂联素是一种丰富的循环血浆蛋白，可抑制高葡萄糖诱导的内皮超氧化物的产生，并增强血管内皮细胞中没有产生。我们和其他人还发现，脂联素在包括内皮细胞在内的各种细胞类型中激活AMP激酶。在这个项目中，我们将表征脂联素在高葡萄糖条件下改善内皮功能的信号传导机制。通过研究体外和肠结肠微血管微血管内皮细胞中的内皮细胞，通过内放显微镜在原位研究，我们将测试以细菌系统中脂联素（GAD）的球状结构域在细菌系统中表达的球状结构域（GAD）在细菌系统中表达的，并在全长脂联蛋白（FAD）中通过抑制型脂肪组成系统表达的细胞（FAD）（FAD）（1）。高葡萄糖，可能是通过蛋白激酶C调节的NAD（P）H氧化酶连接的途径； （2）可能通过高葡萄糖处理的内皮细胞（可能通过AMP激酶连接途径）增强无生产； （3）在高血糖啮齿动物模型的体内改善内皮功能障碍，这是对白细胞 - 内皮相互作用的有益影响，细胞粘附分子的表达和无产生的作用所证明的。研究协作可为我们提供的脂联素基因敲除小鼠，体内研究还将促进，当在无内源性循环脂联素的背景下施用各种形式时，应证明脂联素的血管作用增强。这种体外和体内技术的强大组合将洞悉内皮细胞中脂联素信号转导的洞察力，并可能导致新的靶标，以减少与1型糖尿病相关的增强血管风险。