Oxygen Radicals and Nitric Oxide in Postischemic Injury

缺血后损伤中的氧自由基和一氧化氮

• 批准号: 7097927
• 负责人: JAY Louis ZWEIER
• 金额: $ 48.14万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097927
• 关键词: cardiovascular disorder therapy; cardiovascular pharmacology; cytoprotection; enzyme activity; free radical oxygen; genetically modified animals; intermolecular interaction; isozymes; laboratory mouse; laboratory rat; molecular pathology; myocardial ischemia /hypoxia; nitrates; nitric oxide; nitric oxide synthase; nonhuman therapy evaluation; oxidative stress; superoxides

DESCRIPTION (provided by applicant): Oxygen radicals and nitric oxide (NO) have important roles in cellular signaling and inflammation. Oxygen radical generation is increased in the postischemic heart and is an important cause of postischemic injury. Alterations in NO production also occur and critically contribute to the pathogenesis of postischemic injury. There is increasing evidence that the pathways of oxygen radical and NO generation interact, and that this interaction regulates the cellular production of these critical free radical signaling molecules. However, the exact nature of these interactions and how they modulate postischemic injury is still unknown. Therefore, the goal of this program is to characterize the fundamental interactions between the pathways of oxygen radical and NO generation, and determine how this influences postischemic injury. Studies will be performed first at the enzyme level; then in cells, followed by studies in an in vivo model of coronary occlusion and reflow. There are 5 specific aims. 1) To determine the molecular mechanism by which O2" and O2" -derived oxidants affect the function of NO synthase (NOS). 2) To determine the mechanism by which O2~ and O2~ -derived oxidants alter NOS function in the postischemic heart. 3) To characterize the processes and magnitude of NOS-independent NO generation. 4) To characterize the role of NOS-independent pathways of NO generation in the postischemic heart and the mechanisms that regulate this process. 5) Evaluation of the efficacy of new therapies to inhibit oxidant injury and restore NO and NOS function conferring myocardial protection. For these aims; EPR, electrochemical, and chemiluminescence measurements of oxygen radicals, NO, and NO-derived species will be performed along with characterization of the function, expression and modification of the critical NO generating enzymes. Overall, these experiments will determine the interactions between the molecular and cellular pathways of oxygen radical and NO generation in the in vivo postischemic heart and through this knowledge lead to the development of optimal strategies to prevent postischemic injury.

描述（由申请人提供）：氧自由基和一氧化氮（NO）在细胞信号传导和炎症中具有重要作用。氧气自由基产生在后心脏后心脏增加，是卫星后损伤的重要原因。也没有发生任何生产的改变，并严重促进了缺血后损伤的发病机理。越来越多的证据表明氧自由基和没有产生的途径相互作用，并且这种相互作用调节了这些关键的自由基信号分子的细胞产生。但是，这些相互作用的确切性质及其如何调节缺血后损伤仍然未知。因此，该程序的目的是表征氧基和无产物的途径之间的基本相互作用，并确定这如何影响缺血后损伤。研究将首先在酶水平上进行；然后在细胞中，然后研究冠状动脉闭塞和反流的体内模型。有5个具体目标。 1）确定O2“和O2”衍生的氧化剂影响NO合酶（NOS）功能的分子机制。 2）确定O2〜和O2衍生的氧化剂在后心脏后心脏中改变NOS功能的机制。 3）表征非NOS无产生的过程和幅度。 4）表征没有发电的NOS独立途径在缺血后心脏中的作用以及调节这一过程的机制。 5）评估新疗法抑制氧化剂损伤并恢复NO和NOS功能的疗效。对于这些目标； EPR，电化学和化学发光测量的氧自由基，NO和NO衍生物种将与临界NO产生酶的功能，表达和修饰的表征一起进行。总体而言，这些实验将确定氧自由基的分子和细胞途径之间的相互作用与体内缺血后心脏中没有产生的相互作用，并且通过这种知识导致了预防缺血后损伤的最佳策略。