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、心肌收缩力、Ca2+循环和能量代谢。人们对信号多样性的解码机制给予了很大的关注，但争议仍然很多。半胱氨酸巯基s -亚硝基化是NO发挥作用的主要信号通路。一氧化氮病理生理学的一个新兴概念是一氧化氮和活性氧（ROS）之间的相互作用，即亚硝基/氧化还原平衡，是心血管稳态的重要调节因子。ROS很容易与NO发生反应，限制其生物利用度，并与NO竞争结合到效应分子中的相同位点。我们和其他人已经证明，特定的NO合成酶（NOS）异构体存在于心肌细胞的精确亚细胞器中，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，第一，NOS1在心肌梗死中易位，第二，S-亚硝基化受到S-亚硝基化谷胱甘肽还原酶（S- nitrosoglutathione reductase， GSNOR）的严格调节，该酶分解SNO键，最后，心肌缺血时NO的心脏保护作用至少部分是由Ca+2处理蛋白的S-亚硝基化介导的。这项资助的具体目的是评估1.)NOS同工异构体与GSNOR密切接触，这种密切接触允许s -亚硝基化的严格调节，2)。心肌梗死（MI）后，黄嘌呤氧化酶与NOS1之间存在选择性的、高度调控的相互作用（与NOS3相反）3。GSNOR在心肌梗死后心脏s -亚硝基化调节中起关键作用。我们的工作将为亚硝基/氧化还原平衡在心血管病理生理中的作用提供一个综合的观点。最近的大规模人体研究强调了我们的发现的潜在意义，在这些研究中，对氧化和亚硝化途径的药理学操作对晚期心力衰竭患者产生了有益的影响。

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.