Nitroso/redox balance in myocardial infarction

心肌梗死中的亚硝基/氧化还原平衡

基本信息

批准号：
7775097
负责人：
Joshua M Hare
金额：
$ 44.98万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-02-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7775097
关键词：
Adrenergic Agents Apoptosis Attention Binding Biological Availability Blood Platelets Calcium Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cause of Death Caveolae Cysteine Disease Energy Metabolism Enzymes Equilibrium Functional disorder Generations Grant Health Heart Heart failure Homeostasis Human In Vitro Injury Ischemia Knock-out Left Ventricular Function Left Ventricular Remodeling Mediating Methods Modeling Mus Myocardial Myocardial Infarction Myocardial Ischemia NOS1 gene NOS3 gene Nitric Oxide Nitric Oxide Synthase Organelles Outcome Oxidases Oxidation-Reduction Oxidative Stress Oxidoreductase Pathway interactions Patients Phenotype Play Production Protein Isoforms Proteins Publishing Reactive Oxygen Species Regulation Relaxation Reporting Role SKIL gene Sarcolemma Sarcoplasmic Reticulum Series Signal Pathway Signal Transduction Signaling Molecule Site Source Sulfhydryl Compounds Testing Vascular blood supply Work Xanthine Oxidase adrenergic base improved in vivo inhibitor/antagonist insight mouse S-nitrosoglutathione reductase novel novel therapeutics public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Nitric oxide (NO), a highly versatile signaling molecule, exerts a broad range of regulatory influences in the cardiovascular system that extend from endothelial relaxation to platelet function, myocardial contractility, Ca2+ cycling, and energy metabolism. Much attention has been paid to deciphering mechanisms for such diversity in signaling, but controversy still abounds. S-nitrosylation of cysteine thiols is a major signaling pathway through which NO exerts its actions. An emerging concept of NO pathophysiology is that the interplay between NO and reactive oxygen species (ROS), the nitroso/redox balance, is an important regulator of cardiovascular homeostasis. ROS readily react with NO and limit its bioavailability and also compete with NO for binding to the same sites in effector molecules. We and others have shown that specific NO synthase (NOS) isoforms reside in precise sub-cellular organelles in cardiac myocytes and interact with oxidative enzymes in a spatially confined matter. In this grant we propose experiments that will further elucidate the significance of nitroso/redox balance in health and disease. We will take advantage of 3 newly discovered phenomena, first that NOS1 translocates in myocardial infarction, second that S-nitrosylation is tightly regulated by S- nitrosoglutathione reductase (GSNOR), which decomposes SNO bonds and last, that the well-known cardioprotective effects of NO during myocardial ischemia are mediated at least in part by S-nitrosylation of Ca+2 handling proteins. The specific aims of this grant are to assess that 1.) NOS isoforms are in close contact with GSNOR and this close proximity allows for tight regulation of S-nitrosylation, 2.) After myocardial infarction (MI), there are selective, highly regulated interactions between xanthine oxidase and NOS1 (as opposed to NOS3) 3.) GSNOR plays a pivotal role in regulating S-nitrosylation in the heart after MI. Our work will provide an integrated view of the role of nitroso/redox balance in cardiovascular pathophysiology. The potential implications of our findings are highlighted by recent large-scale human studies where pharmacologic manipulation of oxidative and nitrosative pathways exerted salutary effects in patients with advanced heart failure. PUBLIC HEALTH RELEVANCE: Myocardial infarction occurs when blood supply to the heart is inadequate and this represents the leading cause of death worldwide. In this Grant, we will explore the mechanisms through which the heart protects itself against injury. Our findings will have implications for developing new therapeutic strategies for myocardial infarction and other related common diseases.

描述（由申请人提供）：一种高度用途的信号分子一氧化氮（NO），在心血管系统中发挥广泛的调节影响，从内皮弛豫延伸到血小板功能，心肌收缩力，CA2+循环和能量代谢。人们非常关注解密的信号传导多样性的机制，但争议仍然充斥。半胱氨酸硫醇的S-亚硝基化是一种主要的信号通路，无需发挥其作用。没有病理生理学的一个新兴概念是，硝基/氧化还原平衡NO和活性氧之间的相互作用是心血管稳态的重要调节剂。 ROS很容易反应，并限制其生物利用度，也竞争没有结合效应分子中的相同位点。我们和其他人已经表明，特定的NO合酶（NOS）同工型位于心肌细胞中的精确亚细胞细胞器中，并与空间限制物质中的氧化酶相互作用。在这笔赠款中，我们提出了实验，以进一步阐明硝基/氧化还原平衡在健康和疾病中的重要性。 We will take advantage of 3 newly discovered phenomena, first that NOS1 translocates in myocardial infarction, second that S-nitrosylation is tightly regulated by S- nitrosoglutathione reductase (GSNOR), which decomposes SNO bonds and last, that the well-known cardioprotective effects of NO during myocardial ischemia are mediated at least in part by S-nitrosylation of CA+2处理蛋白质。 The specific aims of this grant are to assess that 1.) NOS isoforms are in close contact with GSNOR and this close proximity allows for tight regulation of S-nitrosylation, 2.) After myocardial infarction (MI), there are selective, highly regulated interactions between xanthine oxidase and NOS1 (as opposed to NOS3) 3.) GSNOR plays a pivotal role in regulating MI后心脏中的S-亚硝基化。我们的工作将对硝基/氧化还原平衡在心血管病理生理学中的作用提供综合的看法。最近的大规模人类研究强调了我们发现的潜在影响，在这种大规模的人类研究中，对氧化和亚硝化途径的药理操纵对患有晚期心力衰竭的患者产生了有益的作用。公共卫生相关性：心肌梗塞发生在心脏的血液供应不足时，这代表了全球死亡的主要原因。在这笔赠款中，我们将探索心脏保护自己免受伤害的机制。我们的发现将对心肌梗死和其他相关常见疾病制定新的治疗策略有影响。