Nitroso/redox balance in myocardial infarction

心肌梗死中的亚硝基/氧化还原平衡

• 批准号: 8399028
• 负责人: Joshua M Hare
• 金额: $ 42.39万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/8399028
• 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; Knockout Mice; 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; S-Nitrosoglutathione; 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; novel; novel therapeutics; public health relevance; research study

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.

说明(申请人提供)：一氧化氮(NO)是一种用途广泛的信号分子，在心血管系统中发挥着广泛的调节作用，从内皮松弛延伸到血小板功能、心肌收缩、钙循环和能量代谢。对这种信号多样性的破译机制已经引起了很大的关注，但争议仍然很多。半胱氨酸硫醇的S亚硝化是NO发挥作用的主要信号途径。NO病理生理学的一个新概念是，NO与活性氧(ROS)之间的相互作用，即亚硝基/氧化还原平衡，是心血管内稳态的重要调节因素。ROS很容易与NO反应，限制了其生物利用度，也与NO竞争结合到效应器分子中的相同位置。我们和其他人已经证明，特定的一氧化氮合酶(NOS)亚型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。在这项拨款中，我们建议进行实验，进一步阐明亚硝基/氧化还原平衡在健康和疾病中的意义。我们将利用3个新发现的现象，第一，NOS1在心肌梗死中的移位；第二，S-亚硝化受到分解SNO键的S-亚硝基谷胱甘肽还原酶的严格调控；最后，众所周知的心肌缺血时NO的保护作用至少部分是通过钙处理蛋白的S-亚硝化来介导的。这笔赠款的具体目的是评估这一点。)NOS异构体与GSNOR密切接触，这种紧密的接触使得对S亚硝化的严格调控成为可能。心肌梗死(MI)后，黄嘌呤氧化酶与NOS1(而不是NOS3)之间存在选择性的、高度调控的相互作用。GSNOR在心肌梗死后心脏S-亚硝化的调节中起着关键作用。我们的工作将提供一个关于亚硝基/氧化还原平衡在心血管病理生理学中的作用的综合观点。最近的大规模人体研究突显了我们发现的潜在意义，在这些研究中，对氧化和亚硝化途径的药物操纵对晚期心力衰竭患者产生了有益的影响。

项目成果

Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit+ Lineages in the Heart.

• DOI: 10.1161/circresaha.115.308061
• 发表时间: 2016-02-05
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Hatzistergos KE;Hare JM
• 通讯作者: Hare JM

Use of mesenchymal stem cells for therapy of cardiac disease.

使用间充质干细胞治疗心脏病。

• DOI: 10.1161/circresaha.116.303614
• 发表时间: 2015-04-10
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Karantalis V;Hare JM
• 通讯作者: Hare JM

Mesenchymal Stem Cells in Cardiology.

• DOI: 10.1007/978-1-4939-3584-0_4
• 发表时间: 2016
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: White IA;Sanina C;Balkan W;Hare JM
• 通讯作者: Hare JM

Mesenchymal Stem Cells as a Biological Drug for Heart Disease: Where Are We With Cardiac Cell-Based Therapy?

• DOI: 10.1161/circresaha.117.306306
• 发表时间: 2015-07-17
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Sanina C;Hare JM
• 通讯作者: Hare JM

Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy.

• DOI: 10.1161/jaha.114.001464
• 发表时间: 2015-03-31
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Bagno LL;Kanashiro-Takeuchi RM;Suncion VY;Golpanian S;Karantalis V;Wolf A;Wang B;Premer C;Balkan W;Rodriguez J;Valdes D;Rosado M;Block NL;Goldstein P;Morales A;Cai RZ;Sha W;Schally AV;Hare JM
• 通讯作者: Hare JM