ENERGETICS OF THE FAILING HEART

衰竭心脏的能量

• 批准号: 6351604
• 负责人: JOANNE S INGWALL
• 金额: $ 28.9万
• 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/6351604
• 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.

心脏衰竭是因为能量匮乏的假说由来已久，但也存在争议。 现在，来自衰竭的人类心肌和严重心力衰竭动物模型的令人信服的证据表明，[ATP] 比正常心肌低约 25%。 这种减少是由于嘌呤池的损失。 基于核磁共振波谱和化学测定的结果，我们和其他人已经表明，组织中磷酸肌酸 (PCr) 和肌酸的含量以及 CK 反应的能力 (Vmax) 也较低。 这些观察结果增加了我们对心脏能量学两个重要方面的理解：ATP 合成动力学和 ATP 利用热力学，即 ATP 消耗反应的化学驱动力。 我们观察到衰竭心脏中的肌酸和嘌呤池较低，这对于理解衰竭心脏的能量学具有重要意义。 由于这些底物的浓度较低，因此它们支持的反应速度也一定较低。然而，肌肉收缩的ATP酶的驱动力可能不会受到损害。 这一新信息引出了以下假设：衰竭心肌中肌酸的损失是一种重要的代偿机制，可以保留 ATP 酶反应的驱动力。 对于衰竭心脏中肌酸转运或从头嘌呤合成的调节知之甚少。 因此，拟议研究计划的主要目标是确定衰竭心脏中肌酸和嘌呤库耗尽的机制。 一个密切相关的目标是操纵正常和衰竭心脏（由于大鼠主动脉带延长）以及由于特定 CK 同工酶基因删除而导致 CK Vmax 较低的心脏中的 ATP/ADP 和 PCr/肌酸比率，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。