Nitroso/redox balance in myocardial infarction

描述（由申请人提供）：一氧化氮（NO）是一种高度通用的信号分子，在心血管系统中发挥广泛的调节作用，从内皮舒张到血小板功能、心肌收缩性、Ca 2+循环和能量代谢。人们对这种信号多样性的破译机制给予了很大的关注，但争议仍然很多。半胱氨酸巯基的S-亚硝基化是NO发挥作用的主要信号通路。NO病理生理学的一个新兴概念是NO和活性氧（ROS）之间的相互作用，亚硝基/氧化还原平衡，是心血管稳态的重要调节剂。ROS容易与NO反应并限制其生物利用度，并且还与NO竞争结合至效应分子中的相同位点。我们和其他人已经表明，特定的一氧化氮合酶（NOS）异构体存在于心肌细胞中精确的亚细胞器中，并在空间受限的物质中与氧化酶相互作用。在这项资助中，我们提出的实验将进一步阐明亚硝基/氧化还原平衡在健康和疾病中的重要性。我们将利用3个新发现的现象，首先是心肌梗死中的NOS 1易位，其次是S-亚硝基谷胱甘肽还原酶（GSNOR）严格调节S-亚硝基化，GSNOR分解SNO键，最后，心肌缺血期间NO的众所周知的心脏保护作用至少部分由Ca+2处理蛋白的S-亚硝基化介导。该补助金的具体目标是评估1。NOS同工型与GSNOR紧密接触，这种紧密接近允许S-亚硝基化的紧密调节，2）。心肌梗死（MI）后，黄嘌呤氧化酶和NOS 1（而不是NOS 3）之间存在选择性的高度调节的相互作用。GSNOR在MI后心脏S-亚硝基化的调节中起关键作用。我们的工作将提供亚硝基/氧化还原平衡在心血管病理生理学中的作用的综合观点。我们的研究结果的潜在影响是突出了最近的大规模的人体研究，药理学操纵的氧化和亚硝化途径发挥有益的效果，在晚期心力衰竭患者。 公共卫生相关性：当心脏血液供应不足时，就会发生心肌梗死，这是全球死亡的主要原因。在这项资助中，我们将探索心脏保护自己免受伤害的机制。我们的研究结果将为心肌梗死和其他相关常见疾病的治疗提供新的策略。

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.