Methylarginines and Vascular Injury

甲基精氨酸和血管损伤

• 批准号: 7568811
• 负责人: Arturo J Cardounel
• 金额: $ 31.9万
• 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/7568811
• 关键词: Affect; Anabolism; Antiatherogenic; Apoptosis; Arginine; Arterial Injury; Atherosclerosis; Biological Availability; Blood Vessels; Cell Proliferation; Cells; 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; new therapeutic target; 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.

这项建议的长期目标是建立二甲基精氨酸二甲氨基水解酶(DDAH)，即 负责甲基精氨酸(MA)代谢的酶，作为血管功能和血管功能的关键调节因子 对伤害的反应。一氧化氮(NO)的生物合成变化与糖尿病的发病机制有关 再狭窄损伤和内源性一氧化氮合酶抑制物ADMA的积聚 和NMMA，是在这些条件下观察到的NO生成减少的原因。我们已经展示了 在兔和大鼠球囊介导的再狭窄损伤模型中，血管DDAH的表达是 随着细胞MA水平的升高而显著降低。对此的总体假设是 认为DDAH表达/活性的丧失导致MA蓄积和NO减少 生物利用度，随后失去抗增殖、抗动脉粥样硬化的特性 维管壁由No.为了验证这一假设，我们将追求以下目标。在目标1中，我们将定义如何 DDAH的调节影响甲基精氨酸水平和随后的一氧化氮合酶衍生的NO和超氧化物歧化 一代。目的2.探讨DDAH在血管损伤中的调节作用及其在动脉中的作用。 改建。这些研究将检验DDAH表达缺失对平滑肌细胞的影响 增殖、迁移和内皮再生。此外，使用携带DDAH的AAV载体 基因，我们将确定DDAH过表达是否可以调节血管重塑过程和 改善血管功能。最终目标将确定甲基精氨酸在动脉粥样硬化形成中的作用。因为 DDAH是由低密度脂蛋白调节的，我们将研究DDAH过表达对启动和 高脂血症状态下动脉粥样硬化的进展。我们相信，这个项目将使DDAH成为 血管损伤反应中的关键成分，可作为血管损伤治疗的新靶点。 血管增生性疾病的治疗。