MECHANISM OF PYRUVATE-DEHYDROGENASE ACTIVATION BY INCREASED CARDIAC WORK
MECHANISM OF PYRUVATE-DEHYDROGENASE ACTIVATION BY INCREASED CARDIAC WORK
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DOI：
10.1016/0022-2828(83)90321-8
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发表时间：
1983-01-01
影响因子：
5
通讯作者：
NEELY, JR
中科院分区：
文献类型：
--
作者：
KOBAYASHI, K;NEELY, JR
在离体灌注大鼠心脏中，研究了增加心脏功、丙酮酸和胰岛素对丙酮酸脱氢酶（PDH）激活状态和丙酮酸脱羧率的影响。在低水平的心脏工作时，当葡萄糖是唯一提供的底物时，61%的PDH以活性形式存在。丙酮酸脱羧的实际速率仅为根据活性PDH百分比计算的可用容量的5%。在这种条件下，糖酵解产生丙酮酸的速度缓慢，限制了丙酮酸脱羧的速度。增加心脏功加速糖酵解，但丙酮酸的产生仍然限制了丙酮酸氧化的速率，并且仅使用了最大PDH容量的40%。在低心脏工作时，胰岛素和葡萄糖的加入将活性PDH的百分比降低到总百分比的16%。胰岛素的这种作用与线粒体NADH/NAD和乙酰辅酶a /辅酶a比值的增加有关。在葡萄糖和胰岛素中，计算出的活性PDH的最大容量与测量到的丙酮酸氧化速率大致相同，表明丙酮酸氧化受到PDH激活状态的限制。在这种情况下，提高心脏工作水平使活性PDH增加到85%，尽管丙酮酸氧化加速，但通过PDH测量的通量仅为活性PDH最大活性的73%。在添加丙酮酸作为外源性底物时，PDH在低心脏功时的活性为82%，这可能是由于丙酮酸抑制PDH激酶。在这种情况下，测定的丙酮酸氧化率是活性PDH容量的64%。然而，心脏工作的增加仍然导致PDH进一步活化，活性达到96%。因此，完整组织中丙酮酸氧化的实际速率取决于单独接受葡萄糖的心脏中丙酮酸的供应，低功同时接受葡萄糖和胰岛素的心脏中活性PDH的百分比，以及高功接受葡萄糖和胰岛素的心脏或以丙酮酸为底物的所有水平的心脏的最终产物抑制。当胰岛素或丙酮酸存在时，随着心脏工作水平的提高，活性PDH的增加与线粒体NADH/NAD比率的降低以及乙酰辅酶a /辅酶a比率的降低密切相关。
The effects of increased cardiac work, pyruvate and insulin on the state of pyruvate dehydrogenase (PDH) activation and rate of pyruvate decarboxylation was studied in the isolated perfused rat heart. At low levels of cardiac work, 61% of PDH was present in the active form when glucose was the only substrate provided. The actual rate of pyruvate decarboxylation was only 5% of the available capacity calculated from the percent of active PDH. Under this condition, the rate of pyruvate decarboxylation was restricted by the slow rate of pyruvate production from glycolysis. Increasing cardiac work accelerated glycolysis, but production of pyruvate remained rate limiting for pyruvate oxidation and only 40% of the maximal PDH capacity was used. Addition of insulin along with glucose reduced the percent of active PDH to 16% of the total at low cardiac work. This effect of insulin was associated withi increased mitochondria NADH/NAD and acetyl CoA/CoA ratios. With both glucose and insulin the calculated maximum capacity of active PDH was about the same as measured rates of pyruvate oxidation indicating that pyruvate oxidation was limited by the activation state of PDH. In this case, raising the level of cardiac work increased the active PDH to 85% and although pyruvate oxidation was accelerated, measured flux through PDH was only 73% of the maximal activity of active PDH. With pyruvate as added exogenous substrate, PDH was 82% of active at low cardiac work probably due to pyruvate inhibition of PDH kinase. In this case, the measured rate of pyruvate oxidation was 64% of the capacity of active PDH. However, increased cardiac work still caused further activation of PDH to 96% active. Thus, actual rates of pyruvate oxidation in the intact tissue were determined by the supply of pyruvate in hearts receiving glucose alone, by the percent of active PDH in hearts receiving both glucose and insulin at low work and by end-product inhibition in hearts receiving glucose and insulin at high work or at all levels of work with pyruvate as substrate. The increase in active PDH with higher levels of cardiac work was closely associated with reduced mitochondrial NADH/NAD ratios and with decreased acetyl CoA/CoA ratios when insulin or pyruvate were present.