Tumor‐Promoting Phorbol Esters Inhibit Cardiac Functions and Induce Redistribution of Protein Kinase C in Perfused Beating Rat Heart
Tumor‐Promoting Phorbol Esters Inhibit Cardiac Functions and Induce Redistribution of Protein Kinase C in Perfused Beating Rat Heart
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促肿瘤佛波醇酯在灌注跳动的大鼠心脏中抑制心脏功能并诱导蛋白激酶 C 重新分布
作者：
S. Yuan;F. Sunahara;A. K. Sen
蛋白激酶C的激活参与了多种细胞反应的调节。虽然我们和其他人已经发现蛋白激酶C及其底物蛋白同时存在于心脏的膜和胞浆部分，但这种激酶在心脏功能调节中的生理作用仍不清楚。在本研究中，我们发现，在大鼠心脏灌流后，给予蛋白激酶C的特异性激活剂佛波酯4β-佛波酯12，13-二丁酸酯和佛波酯12-0-十四酰佛波醇13-乙酸酯，可引起明显的变力和变时性的剂量依赖性负性改变。冠脉流量也呈剂量依赖性减少。甘油二酯类似物1，2-油酰乙酰-甘油和1，2-二辛酰甘油对这些离体心产生与活性佛波酯相似的作用。佛波酯的非活性类似物4α-佛波醇不能产生任何作用。TPA和PDBu在相同的浓度范围内均能激活大鼠心脏细胞膜和胞浆蛋白激酶C的活性。在用PDBu灌流心脏后，还观察到蛋白激酶C从胞浆组分迅速移位到膜组分。我们的发现提供了第一个直接证据，表明蛋白激酶C可能在心脏功能的调节中发挥潜在的重要作用。
Activation of protein kinase C has been implicated in the regulation of a variety of cellular reactions. Although we, and others, have found protein kinase C and its substrate proteins to be present in both membrane and cytosolic fractions in the heart, the physiologic role of this kinase in the regulation of cardiac functions remains unknown. In the present study, we found that in isolated perfused rat heart, administration of phorbol esters 4β-phorbol 12,13-dibutyrate(PDBu) and 12-0-tetradecanoyl-phorbol 13-acetate(TPA), which are specific activators of protein kinase C, produced marked dose-dependent negative changes in inotropy and chronotropy. A dose-dependent decrease in coronary flow was also observed. The diacylglycerol analogues, 1,2-oleoylacetyl-glycerol and 1,2-dioctanoyl-glycerol, produced similar effects as the active phorbol esters on these isolated perfused hearts. An inactive analogue of phorbol ester, 4α-phorbol, failed to produce any effect. Protein kinase C activity in both membrane and cytosolic fractions prepared from rat heart could be activated by TPA and PDBu at the same concentration range as used in the experiments with perfused hearts. Following perfusion of the hearts with PDBu, a rapid translocation of protein kinase C from cytosolic to membrane fractions was also observed. Our findings provide the first direct evidence that protein kinase C may play a potentially important role in the regulation of cardiac functions.
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DOI：
--
发表时间：
1984
期刊：
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DOI：
--
发表时间：
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期刊：
The Journal of biological chemistry
影响因子：
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DOI：
10.1042/bj2090189
发表时间：
1983
期刊：
The Biochemical journal
影响因子：
--
作者：
Katoh,N;Wise,BC;Kuo,JF
通讯作者：
Kuo,JF
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DOI：
10.1016/0006-291x(82)91151-2
发表时间：
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影响因子：
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Kuo,JF