Regulation of Tissue Hemoglobins in the Heart

心脏组织血红蛋白的调节

• 批准号: 7643830
• 负责人: PRADEEP P.A. MAMMEN
• 金额: $ 10.8万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643830
• 关键词: Affect; Biology; Calcineurin; Cardiac; Cardiac Myocytes; Chronic; Cyclic GMP; Data; Development; Engineering; Equilibrium; Functional disorder; Gene Expression; Genes; Genetic Transcription; Goals; Heart; Heart failure; Hemeproteins; Hemoglobin; Homeostasis; Human; Hypoxia; In Vitro; Injury; Knock-out; Knockout Mice; Laboratories; Left; Left Ventricular Dysfunction; Measures; Mediating; Metabolic; Molecular; Mus; Muscle Fibers; Myocardial; Myoglobin; Nitric Oxide; Oxidative Phosphorylation; Pathway interactions; Patients; Promoter Regions; Protein Isoforms; Proteins; Reactive Oxygen Species; Regulation; Research Personnel; Resistance; Role; Signal Transduction; Site; Stress; Therapeutic; Tissues; Transcriptional Regulation; Transgenic Mice; Ventricular; mouse model; novel therapeutics; nuclear factors of activated T-cells; oxygen transport; programs; research study; skeletal

DESCRIPTION (provided by applicant): Myoglobin is a monomeric, cytoplasmic hemoprotein expressed exclusively in cardiomyocytes and oxidative skeletal myofibers. The current paradigm proposes that myoglobin's sole functional role is to mediate oxygen transport within the heart in order to maintain oxidative phosphorylation for myocardial contractility. However, additional functions for myoglobin have been proposed including the role as a cytoprotective protein against reactive oxygen species and as a modulator of nitric oxide (NO). Our laboratory has engineered myoglobin knockout (Mb-/-) mice that are viable and have preserved cardiac function under normoxic conditions due to various cellular and molecular adaptations. We have shown that under chronic hypoxic conditions the Mb-/-mice develop left ventricular (LV) systolic dysfunction due to a NO-mediated, cGMP-independent mechanism. We have also demonstrated that over-expression of myoglobin in the mouse heart confers resistance to ischemic injury. Our overall hypothesis is that myoglobin serves cardioprotective roles in the heart by facilitating oxygen transport and regulating nitric oxide homeostasis within the cardiomyocyte. We will use our genetically modified mouse models to more fully characterize the regulation and function of myoglobin in the heart. Since evidence from human studies suggests there may be dysregulation of myoglobin expression in the failing human heart, our ultimate goal is to determine if augmentation of myoglobin expression and activity can be of therapeutic benefit in heart failure. To enhance our understanding of the regulation and functional roles of myoglobin in the heart, we propose the following three specific aims: 1) To define the mechanism underlying hypoxia-induced LV systolic dysfunction in the myoglobin null mice. 2) To define the cardioprotective mechanism(s) of myoglobin in the heart. 3) To define the transcriptional regulation of myoglobin gene expression under hypoxic conditions. The proposed experiments are hypothesis-driven and will determine the transcriptional regulation and functional roles of myoglobin in the heart. Ultimately, an enhanced understanding of myoglobin biology will provide opportunities for the development of new therapeutic measures in the treatment of patients with advanced heart failure.

描述（由申请人提供）： 肌红蛋白是一种单体的细胞质血红素蛋白，只在心肌细胞和氧化骨骼肌纤维中表达。 目前的范式提出，肌红蛋白的唯一功能作用是介导心脏内的氧转运，以维持氧化磷酸化，从而提高心肌收缩力。 然而，肌红蛋白的其他功能已被提出，包括作为细胞保护蛋白对抗活性氧的作用和作为一氧化氮（NO）的调节剂。 我们的实验室已经设计了肌红蛋白敲除（Mb-/-）小鼠，由于各种细胞和分子适应性，这些小鼠在正常氧条件下存活并保留了心脏功能。 我们已经表明，在慢性缺氧条件下，Mb-/-小鼠由于NO介导的cGMP非依赖性机制而发生左心室（LV）收缩功能障碍。 我们还证明了小鼠心脏中肌红蛋白的过度表达赋予对缺血性损伤的抵抗力。 我们的总体假设是，肌红蛋白通过促进心肌细胞内的氧转运和调节一氧化氮稳态在心脏中发挥心脏保护作用。 我们将使用我们的转基因小鼠模型来更全面地表征肌红蛋白在心脏中的调节和功能。 由于来自人类研究的证据表明，在衰竭的人类心脏中可能存在肌红蛋白表达的失调，因此我们的最终目标是确定肌红蛋白表达和活性的增强是否可以在心力衰竭中具有治疗益处。 为了加深我们对肌红蛋白在心脏中的调节和功能作用的理解，我们提出了以下三个具体目标：1）明确缺氧诱导的心肌收缩功能障碍的机制。 2)明确肌红蛋白在心脏中的心脏保护机制。 3)探讨缺氧条件下肌红蛋白基因表达的转录调控。 拟议的实验是假设驱动的，并将确定肌红蛋白在心脏中的转录调控和功能作用。 最终，对肌红蛋白生物学的进一步了解将为开发治疗晚期心力衰竭患者的新治疗措施提供机会。

项目成果

Molecular insights into the functional role of myoglobin.

• DOI: 10.1007/978-0-387-75434-5_14
• 发表时间: 2007
• 期刊: Advances in experimental medicine and biology
• 作者: D. Garry;P. Mammen

Utility of routine immunofluorescence staining for C4d in cardiac transplant recipients.

心脏移植受者中 C4d 常规免疫荧光染色的效用。

• DOI: 10.1016/j.healun.2009.05.007
• 发表时间: 2009
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Gupta,Sachin;Mitchell,JoshuaD;Lavingia,Bhavna;Ewing,GeneE;Feliciano,MNicholas;Kaiser,PatriciaA;Ring,WSteves;Stastny,Peter;Patel,ParagC;Markham,DavidW;Mammen,PradeepPA;Dimaio,JMichael;Drazner,MarkH
• 通讯作者: Drazner,MarkH

Concentric left ventricular hypertrophy as assessed by cardiac magnetic resonance imaging and risk of death in cardiac transplant recipients.

通过心脏磁共振成像评估同心左心室肥厚和心脏移植受者的死亡风险。

• DOI: 10.1016/j.healun.2010.05.008
• 发表时间: 2010
• 期刊: The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation
• 作者: Patel,ParagC;Reimold,SharonC;Araj,FarisG;Ayers,ColbyR;Kaiser,PatriciaA;Peshock,RonaldM;Yancy,ClydeW;Ring,WSteves;Gupta,Sachin;Mishkin,JosephD;Mammen,PradeepPA;Markham,DavidW;Drazner,MarkH
• 通讯作者: Drazner,MarkH