Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia

心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径

• 批准号: 10794933
• 负责人: Nicole Collins
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10794933
• 关键词: ATP Synthesis Pathway; Acute; Adenine Nucleotides; Anoxia; Automobile Driving; Blood flow; Carbon; Cardiac Myocytes; Cell Respiration; Cell physiology; Citric Acid Cycle; Computer Models; Consumption; Data; Degradation Pathway; Energy Metabolism; Environment; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Experimental Designs; Exposure to; Fumarates; Generations; Goals; Health; Heart; Heart Mitochondria; Hypoxia; Impairment; Infarction; Inosine Monophosphate; Ischemia; Kinetics; Knock-out; Lead; Malate-Aspartate Shuttle Pathway; Malates; Measurement; Metabolic; Metabolism; Mitochondria; Modeling; Muscle; Myocardial; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Myocardium; Organ Transplantation; Oxaloacetates; Oxidants; Oxidative Stress; Oxygen; Pathologic; Pathway interactions; Play; Prevention; Process; Production; Purine Nucleotides; Purines; Rat Transgene; Rattus; Reaction; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Role; Succinate Dehydrogenase; Succinates; Suspensions; System; Testing; Therapeutic; Time; Tissues; Transportation; United States; Vascular blood supply; Work; acronyms; alpha ketoglutarate; experimental study; improved; metabolomics; myocardial damage; predictive modeling; prevent; targeted treatment

Project Summary/Abstract The energy utilized by the heart for contractions is primarily made by aerobic respiration. This process consists of oxidizing carbon substrates to fuel ATP synthesis. An essential substrate is oxygen which acts as the final electron acceptor. Without oxygen, ATP is rapidly depleted from the myocardium. There are a number of scenarios where the heart is exposed to hypoxic or anoxic conditions. Ischemia occurs when blood flow becomes restricted preventing oxygen delivery to part of the muscle. This occurs in ischemic heart disease. If blood flow is not restored in time, it can lead to irreversible damage, termed myocardial infarction. Organ transplantation is another scenario where the heart is away from blood supply during transportation. The amount of time the muscle is without oxygen determines the health of the tissue for the recipient. Situations such as these that involve an ischemic environment induce metabolic changes that damage the myocardium during reperfusion when oxygen is restored, known as ischemia-reperfusion injury. One such change is succinate accumulation. During reperfusion, the immense amount of succinate is responsible for reactive oxygen species (ROS) production that puts oxidative stress on cardiomyocytes. Another metabolic change seen during ischemia is the depletion of adenine nucleotides. This group includes AMP, ADP, and ATP and are all essential energy carriers in the myocardium. The depletion of these molecules results in impaired energy metabolism in the heart. Little is known about the mechanisms behind these metabolic changes. The goal of this project is to uncover the primary pathways of succinate accumulation and adenine nucleotide depletion in ischemic myocardium. The working hypothesis is the combined actions of the tricarboxylic acid (TCA) cycle, malate-aspartate shuttle (MAS), and the purine nucleotide cycle (PNC) provide the substrate utilized for succinate production and adenine nucleotides entering the PNC are shuttled into purine degradation pathways. Experiments involving anoxic isolated heart mitochondrial, ischemic ex vivo hearts, and transgenic rats will be used jointly with computational models of myocardial metabolism to test this hypothesis. The metabolic states of these different systems will be quantified by metabolomics and enzyme inhibitors that will be used to assess primary pathways of accumulation and depletion. Computational models will help with experimental design, refining, and testing hypotheses. The data from this project will have applications for both ischemic heart disease, organ transplantation, treatments for ischemia-reperfusion injury.

项目摘要/摘要 心脏用于收缩的能量主要是由有氧呼吸产生的。这个过程包括 氧化碳底物以燃料ATP合成。必不可少的底物是氧气，充当最终 电子受体。没有氧气，ATP从心肌迅速耗尽。有很多 心脏暴露于低氧或缺氧条件的情况。当血流变成血流时，缺血会发生 限制防止氧气递送到一部分肌肉。这发生在缺血性心脏病中。如果血液流动 没有及时恢复，它可能导致不可逆的损害，称为心肌梗塞。器官移植是 在运输过程中，心脏远离血液供应的另一种情况。肌肉的时间 没有氧气可以决定受体的组织健康。这样的情况涉及 缺血性环境会诱导代谢变化，氧气时损害心肌的代谢变化 已恢复，称为缺血 - 再灌注损伤。一种改变是琥珀酸酯的积累。期间 再灌注，大量的琥珀酸盐负责活性氧（ROS）产生 将氧化应激放在心肌细胞上。缺血期间看到的另一种代谢变化是 腺嘌呤核苷酸。该组包括AMP，ADP和ATP 心肌。这些分子的耗竭会导致心脏中能量代谢受损。鲜为人知 关于这些代谢变化背后的机制。 该项目的目的是发现琥珀酸酯积累和腺嘌呤核苷酸的主要途径 缺血性心肌的耗竭。工作假设是三羧酸的合并作用 （TCA）循环，苹果酸 - 天冬氨酸穿梭（MAS）和嘌呤核苷酸循环（PNC）提供了使用的底物 对于琥珀酸酯的生产和进入PNC的腺嘌呤核苷酸被穿梭为嘌呤降解 途径。涉及缺氧分离的心脏线粒体，缺血性外心脏和转基因的实验 大鼠将与心肌代谢的计算模型共同使用，以检验该假设。这 这些不同系统的代谢状态将通过代谢组学和酶抑制剂进行量化 用于评估积累和耗竭的主要途径。计算模型将有助于 实验设计，完善和测试假设。该项目的数据将具有两者的应用程序 缺血性心脏病，器官移植，缺血再灌注损伤的治疗方法。