Regulation of Tissue Hemoglobins in the Heart

心脏组织血红蛋白的调节

• 批准号: 6961595
• 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 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6961595
• 关键词: cardiac myocytes; cardiovascular pharmacology; cytoprotection; gene expression; gene targeting; genetically modified animals; heart; heart contraction; heart disorder; heart failure; homeostasis; laboratory mouse; myocardial ischemia /hypoxia; myocardium; myoglobin; nitric oxide; oxidative phosphorylation; oxygen transport; pathologic process; protein structure function

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、细胞质的血红蛋白，仅在心肌细胞和氧化骨骼肌纤维中表达。目前的研究范式认为，肌红蛋白的唯一功能是调节心脏内的氧气运输，以维持心肌收缩能力的氧化磷酸化。然而，肌红蛋白的其他功能已经被提出，包括作为抵抗活性氧的细胞保护蛋白的作用和作为一氧化氮(NO)的调节器的作用。我们的实验室已经改造出肌红蛋白基因敲除(Mb-/-)小鼠，这些小鼠可以存活，并由于各种细胞和分子适应而在常氧条件下保留了心脏功能。我们已经证明，在慢性低氧条件下，Mb-/-小鼠由于NO介导的、cGMP非依赖的机制而出现左心室收缩功能障碍。我们还证明，肌红蛋白在小鼠心脏中的过度表达使其对缺血损伤具有抵抗能力。 我们的总体假设是，肌红蛋白通过促进氧运输和调节心肌细胞内一氧化氮的动态平衡，在心脏发挥保护心脏的作用。我们将使用我们的转基因小鼠模型来更全面地描述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，我们的最终目标是确定肌红蛋白表达和活性的增强是否对心力衰竭有治疗作用。为了加深我们对肌红蛋白在心脏中的调节和功能作用的了解，我们提出了以下三个具体目标：1)明确低氧导致肌红蛋白缺失小鼠左室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(S)。3)明确低氧条件下肌红蛋白基因表达的转录调控。 拟议的实验是假说驱动的，将确定肌红蛋白在心脏中的转录调节和功能作用。最终，加强对肌红蛋白生物学的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。