DYNAMICS OF CARDIAC ENERGY METABOLISM

心脏能量代谢动力学

• 批准号: 6308538
• 负责人: JOHANNES H VAN BEEK
• 金额: $ 2.35万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6308538
• 关键词: Mammalia; bioengineering /biomedical engineering; biomedical resource; cardiovascular system; human tissue; model design /development; technology /technique

The goal of this project is to understand the dynamic regulation of cardiac energy metabolism and its effects on heart function in cardiac disease, especially during hypertrophy culminating in heart failure and during myocardial stunning. The time constant of the phosphate metabolites determined with NMR spectroscopy during heart rate steps (3 s) was shorter than the time constant of oxygen consumption (11 s) in the same hearts. We hypothesized that this was due to transitory glycolytic ATP production which delays transport and explains the gap between the 3 and 11 s time constants and retards the transfer of the energetic signal between sites of ATP consumption and the mitochondria. Indeed, when glycolysis was inhibited and bypassed by giving pyruvate as exogenous substrate both time constants became short and the time constant of oxygen consumption was not significantly different from the time constant of inorganic phosphate and phosphocreatine. The time constant of oxygen consumption in response to heart rate steps was also shortened when creatine kinase was inhibited, suggesting that energetic buffering, not only by glycolysis, but also by creatine kinase delays the energetic signal between the sites of ATP consumption and the mitochondria. At 37 degrees Celsius 15 min of ischemia or hypoxia did lead to a substantial increase in the mitochondrial time constant, indicating that energy transfer and/or signaling between energy-consuming sites and mitochondria is deteriorated in stunned myocardium. Reducing the mitochondrial aerobic capacity by selective partial inhibition with oligomycin did not lead to a slower response of oxidative phosphorylation to heart rate steps, suggesting that transcytosolic energy transport rather than mitochondrial processes determine the adaptation speed of oxidative phosphorylation. We found that modest arterial pressure overload for six weeks did not lead to a significant increase in the response time of oxygen consumption, suggesting that energy signaling between sites of ATP consumption and the mitochondria is not yet impaired during mild cardiac hypertrophy.

本项目的目标是了解动态调节 心脏能量代谢及其对心功能的影响 心脏病，尤其是在心脏肥大达到顶峰时 心力衰竭和心肌顿抑。它的时间常量 核磁共振法测定心脏中的磷酸盐代谢产物 速率步长(3 S)小于氧的时间常数 消费(11 S)同心同向。我们假设这是 由于短暂的糖酵解三磷酸腺苷的产生延迟了运输和 解释了S时间常数3和11之间的差距，并延缓了 能量信号在三磷酸腺苷消耗部位之间的传递 线粒体。事实上，当糖酵解被抑制和绕过时 通过给予丙酮酸作为外源底物，这两个时间常数都 耗氧量时间常数短而不是 与无机磷酸盐的时间常数显著不同 和磷酸肌酸。氧气消耗的时间常数 肌酸激酶对心率阶跃的反应也缩短 是被抑制的，这表明能量缓冲不仅通过 糖酵解，但也通过肌酸激酶延迟能量信号 在ATP消耗部位和线粒体之间。37岁 摄氏度15分钟的缺血或缺氧确实会导致 线粒体时间常数显著增加，表明 能源消耗地点之间的能量转移和/或信号 而在顿抑的心肌中，线粒体恶化。减少了 选择性部分抑制线粒体的有氧能力 寡霉素不会导致较慢的氧化反应 磷酸化到心率的步长，表明跨胞浆 能量传输而不是线粒体过程决定了 氧化磷酸化的适应速度。我们发现这是谦虚的 动脉血压超负荷六周并未导致显著的 耗氧量的反应时间增加，表明 ATP消耗部位与线粒体之间的能量信号传递 在轻度心肌肥厚时尚未受损。