Myoglobin as a Nitrite Reductase that Regulates Hypoxic Cardiac NO Signaling

肌红蛋白作为亚硝酸盐还原酶调节缺氧心脏 NO 信号传导

基本信息

  • 批准号:
    8453430
  • 负责人:
  • 金额:
    $ 34.55万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-04-15 至 2014-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): There is an emerging appreciation that heme proteins such as myoglobin and hemoglobin catalyze the metabolism of nitric oxide (NO) and nitrite, and thereby modulate cell and tissue responses to hypoxia. Over the last five years our group has published biochemical and physiological studies that suggest a novel function for hemoglobin as a nitrite reductase that generates NO under physiological and pathological hypoxia, suggesting that myoglobin, the other major heme globin, may also possess a capability to mediate the metabolism of oxides of nitrogen in a manner influenced by oxygen tension. Analogous to the bacterial nitrite reductases, a concerted proton and electron transfer reaction to nitrite reduces the anion to NO. We have also discovered a novel nitrite anhydrase activity that converts two nitrite molecules into the highly diffusible, nitrosating molecule N2O3, allowing efficient NO signaling in a heme rich environment. In the current research proposal, the NO/ N2O3 signaling pathways will be explored in myoglobin, with special focus on an ability to regulate cellular responses to hypoxic and ischemic stress by a) modulating cellular metabolism via the regulation of mitochondrial electron transfer reactions and b) activating net cytoprotective cell signaling reactions after ischemia-reperfusion injury. These concepts will be addressed by testing the hypothesis that myoglobin-mediated nitrite metabolism regulates hypoxic NO signaling and promotes NO bioavailability in the heart. More specifically, using mutant myoglobin proteins in in vitro biochemical and cell culture systems as well as an in vivo model of myocardial infarction, we aim 1) to determine the molecular and enzymatic mechanisms underlying the nitrite reductase activity of myoglobin in hypoxia, 2) define critical molecular targets of myoglobin-derived NO and N2O3, and 3) to determine the role of myoglobin in regulating downstream cytoprotective signaling (apoptosis and mitochondrial biogenesis) after ischemia/reperfusion. Successful completion of the proposed research plan will advance our understanding of the biological function of myoglobin and the physiological and pharmacological potential of nitrite in the cardiovascular system.
描述(申请人提供):有一种新的认识是,血红素蛋白,如肌红蛋白和血红蛋白,催化一氧化氮(NO)和亚硝酸盐的代谢,从而调节细胞和组织对缺氧的反应。在过去的五年里,我们的团队发表了一项生化和生理学研究,表明血红蛋白具有一种新的功能,即在生理和病理缺氧条件下产生NO的亚硝酸盐还原酶,这表明肌红蛋白,另一种主要的血红素球蛋白,也可能具有以受氧分压影响的方式调节氮氧化物新陈代谢的能力。与细菌亚硝酸还原酶类似,亚硝酸根通过质子和电子转移反应将阴离子还原为NO。我们还发现了一种新的亚硝酸脱水酶活性,它能将两个亚硝酸盐分子转化为高度扩散的亚硝化分子N2O,从而在富含血红素的环境中有效地传递NO信号。在目前的研究方案中,将在肌红蛋白中探索NO/N2O3信号通路,特别关注通过a)通过调节线粒体电子转移反应来调节细胞对缺氧和缺血应激的反应的能力,以及b)在缺血再灌注损伤后激活净细胞保护信号反应的能力。这些概念将通过测试肌红蛋白介导的亚硝酸盐代谢调节缺氧性NO信号并促进心脏中NO的生物利用度的假设来解决。更具体地说,利用体外生化和细胞培养系统中的突变肌红蛋白以及在体心肌梗死模型,我们的目标是1)确定缺氧时肌红蛋白亚硝酸盐还原酶活性的分子和酶机制,2)确定肌红蛋白衍生的NO和N2O3的关键分子靶点,以及3)确定肌红蛋白在缺血/再灌注后调节下游细胞保护信号(细胞凋亡和线粒体生物生成)中的作用。成功完成拟议的研究计划将促进我们对肌红蛋白的生物学功能以及亚硝酸盐在心血管系统中的生理和药理潜力的理解。

项目成果

期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Platelet mitochondrial function: from regulation of thrombosis to biomarker of disease.
  • DOI:
    10.1042/bst20120327
  • 发表时间:
    2013-02
  • 期刊:
  • 影响因子:
    3.9
  • 作者:
    Sergey I Zharikov;S. Shiva
  • 通讯作者:
    Sergey I Zharikov;S. Shiva
Nitrite as a mediator of ischemic preconditioning and cytoprotection.
Myoglobin and mitochondria: a relationship bound by oxygen and nitric oxide.
  • DOI:
    10.1016/j.niox.2012.03.005
  • 发表时间:
    2012-05-15
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kamga C;Krishnamurthy S;Shiva S
  • 通讯作者:
    Shiva S
Nitrite: A Physiological Store of Nitric Oxide and Modulator of Mitochondrial Function.
  • DOI:
    10.1016/j.redox.2012.11.005
  • 发表时间:
    2013
  • 期刊:
  • 影响因子:
    11.4
  • 作者:
    Shiva, Sruti
  • 通讯作者:
    Shiva, Sruti
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Mark T Gladwin其他文献

Sodium Nitrite Enhances Pulmonary Epithelial Cells Wound Healing Under Normoxia via Cyclic GMPindependent Signaling Pathways
  • DOI:
    10.1016/j.freeradbiomed.2010.10.276
  • 发表时间:
    2010-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Ling Wang;Mark T Gladwin
  • 通讯作者:
    Mark T Gladwin
1172-74 Pulmonary hypertension is strongly associated with mortality in sickle cell disease: Comparison of echocardiographic outcome predictors
  • DOI:
    10.1016/s0735-1097(04)91779-2
  • 发表时间:
    2004-03-03
  • 期刊:
  • 影响因子:
  • 作者:
    Yukitaka Shizukuda;Vandana Sachdev;Inez Ernst;James S Nichols;Maria Jison;Bernice Brown;William Blackwelder;Griffin P Rodgers;Oswaldo Castro;Frederick P Ognibene;Jonathan P Plehn;Mark T Gladwin
  • 通讯作者:
    Mark T Gladwin
Nitrite-NO bailout for a NOS complex too big to fail
亚硝酸盐 - 一氧化氮救助一个太大而不能倒闭的一氧化氮合酶复合物
  • DOI:
    10.1038/nm.2591
  • 发表时间:
    2011-12-06
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Mark T Gladwin;Jesús Tejero
  • 通讯作者:
    Jesús Tejero
15 - Carbonic Anhydrase Mediated Nitrite Bioactivation
  • DOI:
    10.1016/j.freeradbiomed.2014.10.501
  • 发表时间:
    2014-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Nadeem Wajih;Jun Wang;Xiaohua Liu;Christian Keggi;Amber Lee;Andrea M Belanger;Courtney Sparacino-Watkins;Mark T Gladwin;Daniel B Kim-Shapiro
  • 通讯作者:
    Daniel B Kim-Shapiro
Nitrite as an intrinsic signaling molecule
亚硝酸盐作为一种内在信号分子
  • DOI:
    10.1038/nchembio1005-245
  • 发表时间:
    2005-10-01
  • 期刊:
  • 影响因子:
    13.700
  • 作者:
    Mark T Gladwin
  • 通讯作者:
    Mark T Gladwin

Mark T Gladwin的其他文献

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{{ truncateString('Mark T Gladwin', 18)}}的其他基金

Sickle Cell Disease and Cardiovascular Risk- Red Cell Exchange SCD-CARRE
镰状细胞病和心血管风险 - 红细胞交换 SCD-CARRE
  • 批准号:
    10653703
  • 财政年份:
    2022
  • 资助金额:
    $ 34.55万
  • 项目类别:
1/2 Sickle Cell Disease and CardiovAscular Risk - Red cell Exchange Trial (SCD-CARRE Trial)
1/2 镰状细胞病和心血管风险 - 红细胞交换试验(SCD-CARRE 试验)
  • 批准号:
    10402364
  • 财政年份:
    2019
  • 资助金额:
    $ 34.55万
  • 项目类别:
1/2 Sickle Cell Disease and CardiovAscular Risk - Red cell Exchange Trial (SCD-CARRE Trial)
1/2 镰状细胞病和心血管风险 - 红细胞交换试验(SCD-CARRE 试验)
  • 批准号:
    10165800
  • 财政年份:
    2019
  • 资助金额:
    $ 34.55万
  • 项目类别:
1/2 Sickle Cell Disease and CardiovAscular Risk - Red cell Exchange Trial (SCD-CARRE Trial)
1/2 镰状细胞病和心血管风险 - 红细胞交换试验(SCD-CARRE 试验)
  • 批准号:
    10026435
  • 财政年份:
    2019
  • 资助金额:
    $ 34.55万
  • 项目类别:
Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin
基于突变工程神经球蛋白的吸入一氧化碳中毒解毒剂
  • 批准号:
    10660066
  • 财政年份:
    2014
  • 资助金额:
    $ 34.55万
  • 项目类别:
Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin
基于突变工程神经球蛋白的吸入一氧化碳中毒解毒剂
  • 批准号:
    8801711
  • 财政年份:
    2014
  • 资助金额:
    $ 34.55万
  • 项目类别:
Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin
基于突变工程神经球蛋白的吸入一氧化碳中毒解毒剂
  • 批准号:
    9389399
  • 财政年份:
    2014
  • 资助金额:
    $ 34.55万
  • 项目类别:
Antidote for inhaled CO poisoning based on mutationally engineered neuroglobin
基于突变工程神经球蛋白的吸入一氧化碳中毒解毒剂
  • 批准号:
    8974853
  • 财政年份:
    2014
  • 资助金额:
    $ 34.55万
  • 项目类别:
Translational Pulmonary Vascular Biology
转化肺血管生物学
  • 批准号:
    8337523
  • 财政年份:
    2012
  • 资助金额:
    $ 34.55万
  • 项目类别:
Training in Translational Research and Entrepreneurship in Pulmonary Vascular Biology
肺血管生物学转化研究和创业培训
  • 批准号:
    9906249
  • 财政年份:
    2012
  • 资助金额:
    $ 34.55万
  • 项目类别:

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同时进行有氧运动和认知训练可预防高危老年人的阿尔茨海默病
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