Calcineurin Pathway Is Required for Endothelin-1—Mediated Protection Against Oxidant Stress—Induced Apoptosis in Cardiac Myocytes
作者:
Tsuyoshi,
Kakita Koji,
Hasegawa Eri,
Iwai-Kanai Souichi,
Adachi Tatsuya,
Morimoto Hiromichi,
Wada Teruhisa,
Kawamura Tetsuhiko,
Yanazume Shigetake,
期刊:
Circulation Research: Journal of the American Heart Association
(OVID Available online 2001)
卷期:
Volume 88,
issue 12
页码: 1239-1246
ISSN:0009-7330
年代: 2001
出版商: OVID
关键词: apoptosis;endothelin-1;cardiacmyocyte;calcineurin
数据来源: OVID
摘要:
Endothelin-1(ET-1) acts not only as a growth-promoting peptide but also as a potentsurvival factor against myocardial cell apoptosis. However, the signalingpathways leading to myocardial cell protection by ET-1 are poorly understood.Using a culture system of primary cardiac myocytes derived from neonatal rats,we show in the present study that ET-1 almost completely blocked the hydrogenperoxide-induced increase in the percentage of TdT-mediated dUTP-biotinnick-end labeling-positive myocytes. Apoptosis inhibition by ET-1 wasconfirmed by cytofluorometric analysis as well as by examination of the ladderformation, morphological features, and caspase-3 cleavage. We have found thatET-1 converts the nuclear factor of activated T lymphocytes (NFATc) in cardiacmyocytes into high-mobility forms and translocates cytoplasmic NFATc to thenuclei. In addition, ET-1 stimulates the interaction between NFATc and thecardiac-restricted zinc-finger protein GATA4 in these cells. Theimmunosuppressants cyclosporin A and FK506, which antagonize calcineurin,negated the inhibitory effect of ET-1 on apoptosis. Calcineurin activation denovo was sufficient to inhibit hydrogen peroxide-induced apoptosis. ET-1induced the expression of an antiapoptotic protein bcl-2 in cardiac myocytesin a cyclosporin A-dependent manner, but it did not alter the expression ofbax. Cyclosporin A also attenuated the ET-1-stimulated transcription of thebcl-2 gene in these cells. These findings demonstrate that the calcineurinpathway is required for the inhibitory effect of ET-1 on oxidantstress-induced apoptosis in cardiacmyocytes.
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