Methylarginines and Vascular Injury

甲基精氨酸和血管损伤

• 批准号: 7105251
• 负责人: Arturo J Cardounel
• 金额: $ 33.87万
• 依托单位: OHIO STATE UNIVERSITY
• 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/7105251
• 关键词: aminoacid metabolism; aminohydrolases; arginase; arginine; atherosclerosis; cell migration; cell proliferation; electron spin resonance spectroscopy; enzyme activity; enzyme inhibitors; free radical oxygen; gene expression; hyperlipidemia; laboratory rabbit; laboratory rat; low density lipoprotein; nitric oxide; nitric oxide synthase; pathologic process; restenosis; tissue /cell culture; transfection /expression vector; vascular endothelium; vascular smooth muscle; aminoacid metabolism; aminohydrolases; arginase; arginine; atherosclerosis; cell migration; cell proliferation; electron spin resonance spectroscopy; enzyme activity; enzyme inhibitors; free radical oxygen; gene expression; hyperlipidemia; laboratory rabbit; laboratory rat; low density lipoprotein; nitric oxide; nitric oxide synthase; pathologic process; restenosis; tissue /cell culture; transfection /expression vector; vascular endothelium; vascular smooth muscle

DESCRIPTION (provided by applicant): The long term objective of this proposal is to establish Dimethylarginine Dimethylaminohydrolase (DDAH), the enzyme 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 hypothesis 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 an AAV vector carrying the DDAH gene, we will determine whether DDAH over expression can modulate the vascular remodeling 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.

描述（由申请人提供）：该提案的长期目标是建立二甲基精氨酸二甲基氨基氢化酶（DDAH），该酶是负责甲基金素代谢的酶，作为血管功能的关键调节剂，以及对损伤的反应。一氧化氮（NO）生物合成的改变与再狭窄损伤的发病机理有关，看来内源性一氧化氮合酶抑制剂ADMA和NMMA的积累是导致在这些条件下观察到的降低产生的原因。我们已经表明，在兔子和大鼠模型的伴侣介导的再狭窄损伤中，随着细胞MA水平的同时增加，血管DDAH的表达显着降低。该提议的总体假设是，DDAH表达/活性的丧失导致MA积累，并且没有生物挥舞率降低，随后丧失了抗增殖性抗动脉粥样硬化特性，否NO。为了检验这一假设，我们将追求以下目标。在AIM 1中，我们将定义DDAH的调节如何影响甲基拉氨酸水平以及随后的NOS衍生的NO和超氧化物的产生。在AIM 2中，我们将确定DDAH在血管损伤中的调节及其在动脉重塑中的作用。这些研究将研究DDAH表达丧失对平滑肌细胞增殖，迁移和内皮再生的影响。此外，使用带有DDAH基因的AAV载体，我们将确定DDAH是否可以调节血管重塑过程并改善血管功能。最终目的将确定甲基素金素在动脉粥样硬化中的作用。由于DDAH受LDL的调节，因此我们将研究DDAH对表达对高脂症状下动脉粥样硬化的起始和进展的影响。我们认为，该项目将确立DDAH作为损伤血管反应的关键组成部分，并可以作为治疗血管增生性疾病的新型治疗靶标。