S-nitrosation in cell survival and cell death

S-亚硝化在细胞存活和细胞死亡中的作用

• 批准号: 10308396
• 负责人: Mark Jeffrey Kohr
• 金额: $ 40.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308396
• 关键词: ATP phosphohydrolase; Acute; Address; Amino Acids; Cause of Death; Cell Death; Cell Death Signaling Process; Cell Survival; Complex; Cysteine; Data; Dose; Electron Transport; Exhibits; Female; Genes; Genus Hippocampus; Healthcare; Heart; Heart Mitochondria; Homeostasis; In Situ; Injury; Ischemia; Knowledge; Laboratories; Mammals; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Membrane; Membrane Potentials; Methodology; Methods; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Mus; Mutate; Myocardial; Myocardial Ischemia; Nitric Oxide; Nitrosation; Oxidoreductase; Pathway interactions; Physiological; Play; Premenopause; Production; Protein S; Proteins; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; S-Nitrosoglutathione; Sex Differences; Signal Transduction; Site; Stable Isotope Labeling; Stimulus; Stress; Sulfhydryl Compounds; TRIM Motif; Testing; Therapeutic; Titrations; Translating; United States; Work; base; biological adaptation to stress; cardioprotection; cyclophilin D; in vivo; in vivo Model; insight; male; metabolomics; mitochondrial dysfunction; mitochondrial membrane; nitrosative stress; novel; oligomycin sensitivity-conferring protein; oxidation; preservation; prevent; protein degradation; repaired; response; sex; sex disparity; targeted treatment; therapeutically effective; ubiquitin-protein ligase

PROJECT SUMMARY Myocardial ischemia-reperfusion injury is a leading cause of death in both males and females in the United States. Cardioprotective mechanisms hold promise for lessening this burden, but few experimental discoveries have translated successfully into effective therapeutics. Nitric oxide, produced endogenously or administered exogenously, has been identified as an essential component of many different cardioprotective pathways. Our recent findings suggest that the S-nitrosation (SNO) of cysteine thiols is essential for nitric oxide-dependent protection in female hearts, which exhibit higher baseline SNO levels compared to males and associated with this, greater protection from ischemia-reperfusion injury. SNO levels are regulated by S-nitrosoglutathione reductase (GSNOR), which catabolizes protein SNO, and we have evidence to suggest that GSNOR is a key mediator of protection in the heart. We have also identified two additional targets (TRIM72, mitochondrial proteins) that are critical for the SNO-mediated ischemic stress response in male and female hearts, but specific mechanisms for reducing cell death and potential sex differences are not known. As such, a significant knowledge gap exists regarding a number of fundamental questions related to the physiological and pathophysiological role(s) of SNO signaling in male and female hearts. To address this knowledge gap, we have developed a number of novel methods for the identification and quantitation of specific in situ SNO modification sites in the heart. In the present application, we propose to use these methods in tandem with in vivo and ex vivo models of myocardial ischemia-reperfusion injury and newly developed and emerging methodologies, like in vivo stable isotope labeling by amino acids in mammals (SILAM) to assess protein turnover, quantitative mass spectrometry, and metabolomics analysis. These approaches will be used to enhance our mechanistic understanding of SNO signaling in sex-dependent cardioprotection through the following specific aims: 1) define the role of TRIM72 as a protective target of SNO during ischemia-reperfusion injury, 2) define the protective role of SNO-modified mitochondrial proteins during ischemia-reperfusion injury, and 3) define the role of GSNOR in mitigating nitrosative stress during ischemia-reperfusion injury. If completed successfully, the aims of this proposal will advance our mechanistic understanding of protein SNO signaling in myocardial ischemia- reperfusion injury and cardioprotection. These studies will also provide valuable insight into how SNO-based approaches may be targeted for the therapeutic treatment of ischemic heart disease in both males and females.

项目概要 心肌缺血再灌注损伤是美国男性和女性死亡的主要原因 国家。心脏保护机制有望减轻这种负担，但实验发现很少 已成功转化为有效的治疗方法。一氧化氮，内源性产生或施用 外源性，已被确定为许多不同心脏保护途径的重要组成部分。我们的 最近的研究结果表明，半胱氨酸硫醇的 S-亚硝化（SNO）对于一氧化氮依赖性至关重要 女性心脏的保护，与男性相比，女性心脏表现出更高的基线 SNO 水平，并且与 这可以更好地防止缺血再灌注损伤。 SNO 水平受 S-亚硝基谷胱甘肽调节 还原酶（GSNOR），分解代谢蛋白质 SNO，我们有证据表明 GSNOR 是一个关键 心中的保护中介。我们还确定了两个额外的靶标（TRIM72、线粒体 蛋白质）对于男性和女性心脏中 SNO 介导的缺血应激反应至关重要，但具体 减少细胞死亡和潜在性别差异的机制尚不清楚。因此，一个重要的 在与生理和心理相关的一些基本问题上存在知识差距 SNO 信号在男性和女性心脏中的病理生理学作用。为了解决这一知识差距，我们 开发了许多用于特定原位 SNO 修饰的鉴定和定量的新方法 心中的站点。在本申请中，我们建议将这些方法与体内和体外结合使用 心肌缺血再灌注损伤的体内模型以及新开发和新兴的方法，例如 哺乳动物氨基酸体内稳定同位素标记 (SILAM)，用于评估蛋白质周转、定量质量 光谱分析和代谢组学分析。这些方法将用于增强我们的机制 通过以下具体目标了解 SNO 信号在性别依赖性心脏保护中的作用：1) 定义 TRIM72作为缺血再灌注损伤期间SNO的保护靶点的作用，2）定义保护作用 缺血再灌注损伤期间 SNO 修饰的线粒体蛋白的作用，以及 3) 定义 GSNOR 在 减轻缺血再灌注损伤期间的亚硝化应激。如果成功完成，本次活动的目标 该提案将增进我们对心肌缺血中蛋白质 SNO 信号传导机制的理解 再灌注损伤和心脏保护。这些研究还将提供关于如何基于 SNO 的宝贵见解。 这些方法可以针对男性和女性缺血性心脏病的治疗。

项目成果

Prenatal arsenite exposure alters maternal cardiac remodeling during late pregnancy.

产前亚砷暴露会改变妊娠后期母亲的心脏重塑。

• DOI: 10.1016/j.taap.2024.116833
• 发表时间: 2024-01-22
• 期刊: Toxicology and applied pharmacology
• 影响因子: 3.8
• 作者: Nicole Taube;Raihan Kabir;Obialunanma V. Ebenebe;Haley Garbus;Sarah;Emily J. Illingworth
• 通讯作者: Emily J. Illingworth

Cadmium exposure induces a sex-dependent decline in left ventricular cardiac function.

镉暴露会导致性别依赖性的左心室心脏功能下降。

• DOI: 10.1016/j.lfs.2023.121712
• 发表时间: 2023-04-01
• 期刊: Life sciences
• 影响因子: 6.1
• 作者: Michael Fitch;Raihan Kabir;Obialunanma V. Ebenebe;Nicole Taube;Haley Garbus;P. Sinha;Nadan Wang;Sumita Mishra;B. Lin;Grace K. Muller;Mark J. Kohr
• 通讯作者: Mark J. Kohr

A knock-in mutation at cysteine 144 of TRIM72 is cardioprotective and reduces myocardial TRIM72 release.

TRIM72 半胱氨酸 144 的敲入突变具有心脏保护作用并减少心肌 TRIM72 释放。

• DOI: 10.1016/j.yjmcc.2019.09.008
• 发表时间: 2019-11-01
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: N. Fillmore;Kevin M Casin;P. Sinha;Junhui Sun;Hanley Ma;Jennifer A Boylston;Audrey Noguchi;Chengyu Liu;Nadan Wang;Guangshuo Zhou;Mark J. Kohr;E. Murphy
• 通讯作者: E. Murphy

S-Nitrosoglutathione Reductase Is Essential for Protecting the Female Heart From Ischemia-Reperfusion Injury.

S-亚硝基谷胱甘肽还原酶对于保护女性心脏免受缺血再灌注损伤至关重要。

• 发表时间: 2018
• 影响因子: 20.1
• 作者: Casin, Kevin M;Fallica, Jonathan;Mackowski, Nathan;Veenema, Ryne J;Chan, Ashley;St Paul, Amanda;Zhu, Guangshuo;Bedja, Djahida;Biswal, Shyam;Kohr, Mark J
• 通讯作者: Kohr, Mark J

Long-term effects of prenatal arsenic exposure from gestational day 9 to birth on lung, heart, and immune outcomes in the C57BL/6 mouse model.

从妊娠第 9 天到出生的产前砷暴露对 C57BL/6 小鼠模型的肺、心脏和免疫结果的长期影响。

• 发表时间: 2023-07-01
• 影响因子: 3.5
• 作者: Rychlik, Kristal A;Illingworth, Emily J;Sanchez, Ian F;Attreed, Sarah E;Sinha, Prithvi;Casin, Kevin M;Taube, Nicole;Loube, Jeff;Tasneen, Rokeya;Kabir, Raihan;Nuermberger, Eric;Mitzner, Wayne;Kohr, Mark J;Sillé, Fenna C M
• 通讯作者: Sillé, Fenna C M