ENERGY RESERVE IN THE FAILING MYOCARDIUM

衰竭心肌中的能量储备

• 批准号: 6421861
• 负责人: JOANNE S INGWALL
• 金额: $ 21.47万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2002-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6421861
• 关键词: adenosine triphosphate; bioenergetics; calcium flux; cardiac myocytes; creatine kinase; creatinine; echocardiography; enzyme activity; genetically modified animals; heart contraction; heart failure; heart metabolism; high energy compound; isozymes; laboratory mouse; laboratory rat; nuclear magnetic resonance spectroscopy; phenotype; purine /pyrimidine metabolism; tissue /cell culture

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 25% lower than in normal myocardium and animal models of severe heart failure that the [ATP] is as much as approximately 25% lower than in normal myocardium. We present evidence showing that the 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 (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 of 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.

失败的心脏是能量饥饿的假设既是长期的又是有争议的。现在有令人信服的证据来自失败的人体心肌和严重心力衰竭的动物模型，即[ATP]比正常心肌和严重心力衰竭的动物模型低25％，而[ATP]比正常心肌低约25％。我们提供的证据表明，减少是由于嘌呤池的损失。基于使用NMR光谱和化学测定的结果，我们和其他人表明，磷酸氨酸（PCR）和肌酸的组织含量以及CK反应（VMAX）的能力也较低。这些观察结果提高了我们对心脏能量学（PCR）和肌酸的两个重要方面的理解，而CK反应（VMAX）的能力也较低。这些观察结果提高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ATP消耗反应的化学驱动力。我们的观察到，肌酸和嘌呤池在失败的心脏中较低，对理解失败的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的速度必须较低。但是，肌肉收缩的ATPase的驱动力可能不会受到损害。这一新信息导致了以下假设：失败的心肌中肌酸的丧失是保留ATPase反应驱动力的重要补偿机制。关于在失败的心脏中的肌酸运输或从头嘌呤合成的调节知之甚少。因此，拟议的研究计划的主要目标是定义肌酸和嘌呤池在失败的心脏中耗尽的机制。 一个密切相关的目标是在正常和失败的心脏（由于大鼠中长时间主动脉谱带）以及患有低CK VMAX的心脏中的ATP/ADP和PCR/肌酸比率操纵，由特定CK Insozymes的基因删除引起的CK VMAX较低的心脏，以确定失败的心脏不再能够支持正常合同效果和合同均值的能力。