ENERGETICS OF THE FAILING HEART

衰竭心脏的能量

• 批准号: 6629056
• 负责人: JOANNE S INGWALL
• 金额: $ 30.08万
• 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 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6629056
• 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.

衰竭的心脏是能量缺乏的假说既存在已久，也存在争议。 现在有令人信服的证据，从失败的人类心肌和严重心力衰竭的动物模型中，[ATP]比正常心肌低约25%。 这种减少是由于嘌呤池的损失。 基于使用NMR光谱和化学分析的结果，我们和其他人已经表明，磷酸肌酸（PCr）和肌酸的组织含量以及CK反应的能力（Vmax）也较低。 这些观察增加了我们对心脏能量学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ATP消耗反应的化学驱动力。 我们的观察，肌酸和嘌呤池是较低的衰竭的心脏有重要意义的理解衰竭的心脏能量。 由于这些底物的浓度较低，它们支持的反应速度必须较低。然而，肌肉收缩的ATP酶的驱动力可能不会受到损害。 这一新的信息导致了以下假设：在衰竭心肌中肌酸的损失是一种重要的代偿机制，保留了ATP酶反应的驱动力。 对于衰竭心脏中肌酸转运或嘌呤从头合成的调节知之甚少。 因此，拟议的研究计划的主要目标是确定肌酸和嘌呤池在衰竭心脏中耗尽的机制。 一个密切相关的目标是操纵ATP/ADP和PCr/肌酸比值在正常和衰竭的心脏（由于延长主动脉束带大鼠），并在心脏与低CK Vmax所造成的基因缺失的特定CK同工酶，以确定能量状态衰竭的心脏不再能够支持正常的收缩性能和收缩储备。

项目成果

Is creatine kinase a target for AMP-activated protein kinase in the heart?

• DOI: 10.1006/jmcc.2002.2062
• 发表时间: 2002-09-01
• 期刊: JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
• 影响因子: 5
• 作者: Ingwall, JS

The fall in creatine levels and creatine kinase isozyme changes in the failing heart are reversible: complex post-transcriptional regulation of the components of the CK system.

衰竭心脏中肌酸水平的下降和肌酸激酶同工酶的变化是可逆的：CK 系统成分的复杂转录后调节。

• DOI: 10.1016/j.yjmcc.2005.05.003
• 发表时间: 2005
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Shen,Weiqun;Spindler,Matthias;Higgins,MarnieA;Jin,Najia;Gill,RobertM;Bloem,LauraJ;Ryan,TimothyP;Ingwall,JoanneS
• 通讯作者: Ingwall,JoanneS

Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T.

• DOI: 10.1172/jci15967
• 发表时间: 2003-09
• 期刊: The Journal of clinical investigation
• 作者: M. Javadpour;J. Tardiff;I. Pinz;J. Ingwall