Role of protein S-nitrosation in cardioprotection

蛋白质S-亚硝化在心脏保护中的作用

• 批准号: 8085866
• 负责人: Mark Jeffrey Kohr
• 金额: $ 5.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2012-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085866
• 关键词: ATP phosphohydrolase; Aconitate Hydratase; Address; Cardiac; Cardiac Myocytes; Coronary artery; Cyclic GMP; Cysteine; Exhibits; Female; Functional disorder; Health; Heart; Human; Infarction; Injury; Ischemia; Ischemic Preconditioning; Lead; Literature; Measures; Mitochondria; Modification; Myocardial Stunning; Myocardium; Nitric Oxide; Nitric Oxide Synthase; Nitrosation; Patients; Physiological; Play; Post-Translational Protein Processing; Production; Protein S; Proteins; Reperfusion Injury; Reporting; Role; S-Nitrosothiols; Signal Pathway; Source; Sulfhydryl Compounds; Therapeutic Intervention; Ventricular Arrhythmia; ketoglutarate dehydrogenase; novel; oxidation; oxidative damage; research study

DESCRIPTION (provided by applicant): The purpose of this proposal is to elucidate the mechanism whereby S-nitrosation (SNO) confers cardioprotection from ischemia-reperfusion injury. S-nitrosation is a recently described protein modification in which a nitric oxide moiety is covalently attached to a thiol group of a cysteine residue, leading to the formation of S-nitrosothiols. SNO is a reversible modification that has been shown to modify the activity of target proteins. Additionally, SNO has been reported to protect thiol groups from oxidative damage. Potential sources for the endogenous production of nitric oxide in cardiac myocytes include nitric oxide synthase and non-enzymatic means. Brief occlusion of a coronary artery generally results in cardiac ischemia-reperfusion injury. This type of injury can lead to cardiac dysfunction, which is initially reversible (myocardial stunning) and later irreversible (infarction), and ventricular arrhythmias. However, cardioprotective effects result from ischemic preconditioning, a protective mechanism of the heart that develops from several brief episodes of ischemia. This cardioprotective measure has been reported to increase S-nitrosation formation in the cardiac myocyte. Furthermore, hearts from females exhibit endogenous cardioprotection, which has been shown to be NOS-dependent. However, studies have yet to fully characterize the signaling pathways necessary for SNO formation or the mechanism(s) through which SNO formation exerts cardioprotection. Therefore, further studies are needed in order to examine the role of S-nitrosation in cardioprotection. The role of S-nitrosation will be addressed in the specific aims of this proposal and are as follows: 1) determine the specific signaling pathways that are necessary for S-nitrosation formation in cardioprotection, 2) identify the specific cysteine residues that are SNO during cardioprotection, and 3) determine if S-nitrosation exerts cardioprotective effects by shielding critical thiol groups from oxidative damage. The overall hypotheses of this proposal are as follows: 1.) SNO formation and cardioprotection is initiated upon activation of specific signaling pathways, 2.) SNO occurs at specific cysteine residues on key target proteins, and 3.) SNO provides cardioprotection by blocking against oxidative damage. PUBLIC HEALTH RELEVANCE: The specific aims of the proposed study will determine the role of S-nitrosation in cardioprotection and resolve the mechanism through which S- nitrosation serves to protect against ischemia-reperfusion injury. These results will also help to clarify inconsisties in the literature that relate to the role of nitric oxide synthase in cardioprotection. Additionally, these results may allow for improvements in the treatment of human cardiac patients by identifying novel targets for therapeutic intervention.

描述（由申请人提供）：本提案的目的是阐明s -亚硝化（SNO）保护心脏免受缺血再灌注损伤的机制。s -亚硝化是最近描述的一种蛋白质修饰，其中一氧化氮部分共价附着在半胱氨酸残基的巯基上，导致s -亚硝基硫醇的形成。SNO是一种可逆修饰，已被证明可以修饰靶蛋白的活性。此外，据报道SNO可以保护巯基免受氧化损伤。心肌细胞内源性一氧化氮的潜在来源包括一氧化氮合酶和非酶手段。冠状动脉的短暂闭塞通常会导致心脏缺血再灌注损伤。这种类型的损伤可导致心功能障碍，最初是可逆的（心肌昏迷），后来是不可逆的（梗死），以及室性心律失常。然而，心脏保护作用来自缺血预处理，这是一种心脏保护机制，由几次短暂的缺血发作发展而来。据报道，这种心脏保护措施可增加心肌细胞中s -亚硝化的形成。此外，来自女性的心脏表现出内源性心脏保护，这已被证明是nos依赖的。然而，研究尚未完全描述SNO形成所需的信号通路或SNO形成发挥心脏保护作用的机制。因此，需要进一步研究s -亚硝化在心脏保护中的作用。s -亚硝化的作用将在本提案的具体目标中得到解决，具体目标如下：1)确定在心脏保护过程中形成s -亚硝化所必需的特定信号通路，2)确定在心脏保护过程中是SNO的特定半胱氨酸残基，以及3)确定s -亚硝化是否通过屏蔽关键巯基免受氧化损伤而发挥心脏保护作用。本提案的总体假设如下：1)SNO的形成和心脏保护是在特定信号通路激活后启动的，2)。2 . SNO发生在关键靶蛋白的特定半胱氨酸残基上。SNO通过阻止氧化损伤提供心脏保护。公共卫生相关性：该研究的具体目的是确定S-亚硝化在心脏保护中的作用，并解决S-亚硝化对缺血再灌注损伤的保护机制。这些结果也将有助于澄清与一氧化氮合酶在心脏保护中的作用有关的文献中的不一致之处。此外，这些结果可能通过确定治疗干预的新靶点来改善人类心脏病患者的治疗。

项目成果

Effect of sodium nitrite on ischaemia and reperfusion-induced arrhythmias in anaesthetized dogs: is protein S-nitrosylation involved?

• DOI: 10.1371/journal.pone.0122243
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kovács M;Kiss A;Gönczi M;Miskolczi G;Seprényi G;Kaszaki J;Kohr MJ;Murphy E;Végh Á
• 通讯作者: Végh Á