Myeloperoxidase and NO signaling in the vasculature

脉管系统中的髓过氧化物酶和 NO 信号传导

• 批准号: 6763077
• 负责人: C Roger WHITE
• 金额: $ 28.7万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-20 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6763077
• 关键词: arginine; cardiovascular function; enzyme activity; enzyme inhibitors; free radical scavengers; hydrogen peroxide; ischemia; laboratory rat; myeloperoxidase; nitric oxide; nitric oxide synthase; oxidative stress; reperfusion; vascular endothelium

DESCRIPTION (provided by the applicant): The heme protein myeloperoxidase (MPO) plays an important role in the host defense response. Myeloperoxidase catalyzes the addition of chloride to hydrogen peroxide, resulting in the formation of the chlorinating species hypochlorous acid (HOCI) Hypochlorous acid reacts avidly with numerous cellular targets including thiols, amines, nucleotides and unsaturated fatty acids. Recent evidence suggests that MPO and HOCI contribute to the pathogenesis of cardiovascular disease. In this application, we present data suggesting that MPO-derived HOCI contributes to the development of endothelial dysfunction by reducing nitric oxide (NO) bioavailability. MPO effectively binds to the arterial wall and is associated with a significant increase in tissue enzymatic activity. Results of in vitro studies showed that MPO-derived HOCI impairs acetylcholine-induced relaxation but does not affect relaxation induced by an NO donor. These data suggest that the endothelium is a target of MPO-dependent injury. HOCI mediates the inhibitory effects of MPO since endothelial dysfunction could be prevented by addition of the HOC scavenger L-methionine. There are several components of the endothelial NO synthetic pathway that may be modified by HOCI including NO synthase (NOS III) activity, L-arginine substrate and NOS Ill-dependent cofactors. In this proposal, we will identify mechanisms underlying the inhibitory effects of MPO-derived HOCI on NO bioavailability by 1) defining the effects of MPO on endothelial NO signaling processes; 2) characterizing the role of L-arginine derived N-chloramines in MPO-dependent endothelial cell injury; and 3) by determining whether inhibitors of MPO prevent endothelial dysfunction in a rodent model of ischemia-reperfusion. The HOCI-dependent modification of L-arginine may represent a common pathogenic mechanism underlying endothelial dysfunction in diverse cardiovascular diseases.

描述（由申请人提供）：血红素蛋白髓过氧化物酶（MPO） 在东道国防御反应中起着重要作用。脊髓过氧化物酶催化 将氯化物添加到过氧化氢中，导致形成 氯化物种次氯酸（HOCI）次伐多酸反应 狂热地拥有许多细胞靶标，包括硫醇，胺，核苷酸和 不饱和脂肪酸。最近的证据表明MPO和HOCI贡献 心血管疾病的发病机理。在此应用程序中，我们提出 数据表明，MPO衍生的HOCI有助于发展 通过减少一氧化氮（NO）生物利用度，内皮功能障碍。 MPO 有效地与动脉壁结合，并与显着相关 组织酶活性的增加。体外研究的结果表明 MPO衍生的HOCI会损害乙酰胆碱引起的松弛，但不会影响 没有捐助者引起的放松。这些数据表明内皮是 MPO依赖性损伤的靶标。 HOCI介导了MPO的抑制作用 由于可以通过添加HOC来预防内皮功能障碍 清道夫l-methionine。内皮号有几个组成部分 HOCI可以修改的合成途径包括无合酶（NOS III） 活性，L-精氨酸底物和非依赖性辅助因子。在这个 提案，我们将确定抑制作用的基础机制 MPO衍生的HOCI无生物利用度，通过1）定义MPO的影响 内皮无信号过程； 2）表征L-精氨酸的作用 在MPO依赖性内皮细胞损伤中衍生的N-氯胺； 3） 确定MPO的抑制剂是否防止了内皮功能障碍 缺血再灌注的啮齿动物模型。 HOCI依赖性修饰 L-精氨酸可能代表内皮内皮的常见致病机制 各种心血管疾病的功能障碍。