Endothelial Dysfunction in Insulin Resistance

胰岛素抵抗中的内皮功能障碍

• 批准号: 7145530
• 负责人: DAVID W BUSIJA
• 金额: $ 32.29万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145530
• 关键词: NAD(P)H dehydrogenase; antihypercholesterolemic agent; biological signal transduction; blood vessel disorder; brain circulation; cardiovascular pharmacology; cerebral ischemia /hypoxia; diabetic angiopathy; enzyme activity; free radical oxygen; genetic models; inflammation; insulin sensitivity /resistance; laboratory rat; membrane potentials; molecular pathology; pharmacokinetics; potassium channel; stroke; superoxide dismutase; transfection; vascular endothelium; vascular smooth muscle; vasomotion

DESCRIPTION (provided by applicant): Our recent studies show that insulin resistance (IR) severely impairs arterial dilator function in the cerebral circulation via mechanisms involving the sustained production and actions of reactive oxygen species (ROS). Our overall hypothesis is that: Vascular dysfunction of the cerebral circulation in IR is due to augmented ROS levels from enhanced activity of the NADPH oxidase system. Furthermore, we speculate that differences are present in ROS signaling occur in endothelium and VSM; that statins directly modulate NADPH oxidase activity or indirectly act via a reduction in vascular inflammation; that ROS scavenging by superoxide dismutase or gene transfer of EcSOD reverses vascular dysfunction; that neurological damage is enhanced in IR; and that acute administration of statins can limit IR-enhanced ischemic damage in IR. We have created 2 specific aims to test the following hypotheses and speculations in the cerebral circulation and brain in a genetic model of IR (Zucker obese rats): Specific Aim 1. Elucidation of mechanisms of deranged arterial function of the cerebral circulation in IR. We will test the hypothesis that IR impairs endothelium- and VSM potassium channel-dependent function of cerebral arteries via vascular production and actions of ROS. First, we will assess the role of ROS in vascular dysfunction in IR using pharmacological agents and gene transfer approaches. Second, we will determine the metabolic source and characteristics of ROS involved in dysfunction of cerebral vessels of IR rats. Third, we will document, using electrophysiological approaches, the effects of ROS on potassium channels-dependent membrane potential characteristics in cerebral arteries from IR rats. Fourth, we will examine the effects of IR on extent of neurological injury following experimental strokes. Specific Aim 2. Examination of mechanism of statins in reversing vascular dysfunction in IR. We will test the hypothesis that statins directly modulate NADPH oxidase activity in IR. First, we will assess the dynamics of statin effects on vascular responsiveness in IR. Second, we will determine the effects of statins on indices of vascular inflammation and ROS production in cerebral arteries. Third, we will examine the effects of statins and IR on VSM membrane characteristics. Fourth, we will examine the effects of statins on the extent of stroke damage in IR. We believe that our results will lead to new therapies that will help patients with insulin resistance and vascular dysfunction.

描述（由申请人提供）：我们最近的研究表明，胰岛素抵抗（IR）通过涉及持续生产和活性氧（ROS）的持续生产和作用的机制严重损害了动脉扩张器的功能。我们的总体假设是：IR中脑循环的血管功能障碍是由于NADPH氧化酶系统的增强活性所致。此外，我们推测ROS信号中存在差异，并在内皮和VSM中发生。他汀类药物直接通过减少血管炎症来调节NADPH氧化酶活性或间接起作用。通过超氧化物歧化酶或ecsod的基因转移的ROS逆转了血管功能障碍； IR中的神经系统损害得到了增强。他汀类药物的急性给药可以限制IR中IR增强的缺血性损害。我们创建了2个特定的目的，以测试IR遗传模型（Zucker肥胖大鼠）的脑循环和大脑中的以下假设和猜测：特定目标1。阐明IR中脑循环的动脉动脉功能机制。我们将检验以下假设：IR会通过血管生产和ROS的作用来损害脑动脉的内皮和VSM钾通道依赖性功能。首先，我们将使用药理学剂和基因转移方法评估ROS在IR中血管功能障碍中的作用。其次，我们将确定IR大鼠脑血管功能障碍的ROS的代谢来源和特征。第三，我们将使用电生理方法记录ROS对IR大鼠脑动脉中钾通道依赖性膜电位特征的影响。第四，我们将检查IR对实验性中风后神经损伤程度的影响。具体目的2。在逆转IR的血管功能障碍时，他汀类药物的机制检查。我们将检验以下假设：他汀类药物直接调节IR中的NADPH氧化酶活性。首先，我们将评估他汀类药物对IR血管反应的影响的动态。其次，我们将确定他汀类药物对脑动脉血管炎症和ROS产生指标的影响。第三，我们将研究他汀类药物和IR对VSM膜特征的影响。第四，我们将研究他汀类药物对IR中风损伤程度的影响。我们认为，我们的结果将导致新的疗法，这些疗法将帮助患有胰岛素抵抗和血管功能障碍的患者。