Methylarginines and Vascular Injury

甲基精氨酸和血管损伤

• 批准号: 7369819
• 负责人: Arturo J Cardounel
• 金额: $ 32.25万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7369819
• 关键词: Affect; Anabolism; Antiatherogenic; Apoptosis; Arginine; Arterial Injury; Atherosclerosis; Biological Availability; Blood Vessels; Cell Proliferation; Cells; Condition; Disease; Electron Spin Resonance Spectroscopy; Electrons; Endothelial Cells; Enzymes; Functional disorder; Funding; Generations; Genes; Homeostasis; Hydrolase; Hypertension; Injury; Lead; Low-Density Lipoproteins; Measurement; Mediating; Metabolism; Minority; Modeling; Molecular; Natural regeneration; Nitric Oxide; Nitric Oxide Synthase; Oryctolagus cuniculus; Pathogenesis; Physiological; Play; Process; Property; Rattus; Reactive Oxygen Species; Regulation; Research Personnel; Role; Smooth Muscle; Smooth Muscle Myocytes; Superoxides; Testing; United States National Institutes of Health; Vascular remodeling; Vasodilator Agents; adeno-associated viral vector; arterial remodeling; atherogenesis; base; dimethylarginine; hypercholesterolemia; improved; in vivo Model; inhibitor/antagonist; migration; mouse Smc1l1 protein; mouse Smc1l2 protein; novel therapeutics; programs; response to injury; restenosis; therapeutic target

The long term objective of this proposal is to establish Dimethyarginie Dimethylaminohydrolase (DDAH), the enyme responsible for methylarginine (MA) metabolism, as a key regulator of vascular function and the response to injury. Altered nitric oxide (NO) biosynthesis has been implicated in the pathogenesis of restenosis injury and it appears that accumulation of the endogenous nitric oxide synthase inhibitors, ADMA and NMMA, are responsible for the reduced NO generation observed in these conditions. We have shown that in both rabbit and rat models of balloon- mediated restenosis injury, vascular DDAH expression is significantly decreased with a concomitant increase in cellular MA levels. The overall hypothesis of this proposal is that the loss of DDAH expression/activity results in MA accumulation and decreased NO bioavailabilty with subsequent loss of the anti-proliferative anti-atherogenic properties afforded to the vascular wall by NO. To test this hypotheis we will pursue the following aims. In aim 1, we will define how modulation of DDAH affects methylarginine levels and subsequent NOS-derived NO and superoxide generation. In aim 2. we will determine the modulation of DDAH in vascular injury and its role in arterial remodeling. These studies will examine the effects of loss of DDAH expression on smooth muscle cell proliferation, migration and endothelial regeneration. In addition, using and AAV vector carrying the DDAH gene, we will determine whether DDAH over expression can modulate the vascular remodelling process and improve vascular function. The final aim will determine the role methylarginines in atherogenesis. Because DDAH is regulated by LDL, we will study the effects of DDAH over expression on the initiation and progression of atherosclerosis in the hyperlipidemic state. We believe that this project will establish DDAH as a critical component in the vascular response to injury and may serve as a novel therapeutic target in the treatment of vasculoproliferative disorders.

该提议的长期目标是建立二甲基二甲基氨基氢化酶（DDAH）， 负责甲基精氨酸（MA）代谢的燃料，作为血管功能的关键调节剂和 对伤害的反应。一氧化氮（NO）生物合成的改变已与 再狭窄损伤，似乎内源性一氧化氮合酶抑制剂的积累ADMA 和NMMA，负责在这些条件下没有观察到的降低。我们已经显示了 在兔子和大鼠模型的气囊介导的再狭窄损伤中，血管DDAH表达是 随着细胞MA水平的同时增加，显着下降。总体假设 建议是DDAH表达/活动的丧失导致MA积累，而NO降低 随后丧失了抗增殖性抗动脉生基因特性 血管壁否。为了检验这种假设，我们将追求以下目标。在AIM 1中，我们将定义如何 DDAH的调节会影响甲基精氨酸水平以及随后的NOS衍生NO和超氧化物 一代。在AIM 2中。我们将确定DDAH在血管损伤中的调节及其在动脉中的作用 重塑。这些研究将检查DDAH表达丧失对平滑肌细胞的影响 增殖，迁移和内皮再生。此外，使用和携带DDAH的AAV矢量 基因，我们将确定表达上的DDAH是否可以调节血管重塑过程和 改善血管功能。最终目的将确定甲基素金素在动脉粥样硬化中的作用。因为 DDAH受LDL的调节，我们将研究DDAH对表达对启动的影响 高脂血症状态下动脉粥样硬化的进展。我们认为这个项目将确定DDAH 血管对损伤的重要组成部分，可以作为新的治疗靶点 血管增生性疾病的治疗。