ENERGETICS OF THE FAILING HEART

衰竭心脏的能量

• 批准号: 6499038
• 负责人: JOANNE S INGWALL
• 金额: $ 29.48万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499038
• 关键词: adenine; adenosine triphosphate; adenosinetriphosphatase; analog; bioenergetics; cardiac myocytes; chemical kinetics; creatine; creatine kinase; creatine phosphate; enzyme activity; genetically modified animals; glycine; heart contraction; heart failure; laboratory mouse; nuclear magnetic resonance spectroscopy; physiologic stressor; thermodynamics; transport proteins; western blottings

The hypothesis that the failing heart is energy starved is both long-standing and controversial. There is now convincing evidence from both failed human myocardium and animal models of severe heart failure that the [ATP] is as much as approximately 25 percent lower than in normal myocardium. This decrease is due to a loss of the purine pool. Based on results using NMR spectroscopy and chemical assay, we and others have shown that the tissue contents of phosphocreatine (PCr) and creatine and the capacity of the CK reaction (Vmax) are also lower. These observations increase our understanding of two important aspects of cardiac energetics: the kinetics of ATP synthesis and the thermodynamics of ATP utilization, i.e. the chemical driving force for the ATP-consuming reactions. Our observations that the creatine and purine pools are lower in the failing heart have important implications for understanding the energetics of the failing heart. Because the concentrations of these substrates are lower, the velocities of the reactions they support must be lower. However, the driving force for ATPases of muscle contraction may not be compromised. This new information leads to the following hypothesis: that the loss of creatine in the failing myocardium is an important compensatory mechanism, preserving the driving force for the ATPase reactions. Little is known about the regulation of either creatine transport or de novo purine synthesis in the failing heart. Accordingly, the primary goal of the proposed research plan is to define the mechanisms whereby creatine and purine pools are depleted in the failing heart. A closely related goal is to manipulate the ATP/ADP and PCr/creatine ratios in normal and failing hearts (due to prolonged aortic banding in the rat), and in hearts with low CK Vmax caused by gene deletions of specific CK isozymes, to define the energetic state of the failing heart no longer capable of supporting normal contractile performance and contractile reserve.

心脏衰竭是能量匮乏的假设由来已久，也存在争议。现在，来自衰竭的人类心肌和严重心力衰竭的动物模型的令人信服的证据表明，[ATP]比正常心肌低约25%。这一下降是由于嘌呤池的损失。根据核磁共振波谱和化学分析的结果，我们和其他人发现，组织中磷酸肌酸(PCr)和肌酸的含量以及CK反应能力(Vmax)也较低。这些观察加深了我们对心脏能量学的两个重要方面的理解：ATP合成的动力学和ATP利用的热力学，即消耗ATP反应的化学驱动力。我们观察到衰竭心脏的肌酸和嘌呤水平较低，这对理解衰竭心脏的能量学有重要意义。因为这些底物的浓度较低，它们支持的反应速度肯定较低。然而，肌肉收缩的ATPase的驱动力可能不会受到影响。这一新信息导致了以下假设：衰竭心肌中肌酸的丢失是一种重要的代偿机制，保留了ATPase反应的驱动力。在衰竭的心脏中，肌酸转运或从头合成嘌呤的调节知之甚少。因此，拟议的研究计划的主要目标是确定衰竭心脏中肌酸和嘌呤池耗尽的机制。一个密切相关的目标是控制正常和衰竭心脏(由于大鼠主动脉缩窄延长所致)以及因特定CK同工酶基因缺失而导致CK Vmax降低的心脏的ATP/ADP和PCr/肌酸比值，以确定不再能够支持正常收缩性能和收缩储备的衰竭心脏的能量状态。