Circulation Research. 2001
Published online before print June 7, 2001, doi: 10.1161/hh1201.091794
Published online before print June 7, 2001, doi: 10.1161/hh1201.091794
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© 2001 American Heart Association, Inc.
Article |
Calcineurin Pathway Is Required for Endothelin-1–Mediated Protection Against Oxidant Stress–Induced Apoptosis in Cardiac Myocytes
From the Department of Cardiovascular Medicine (T. Kakita, K.H., E.I.-K., T.M., H.W., T. Kawamura, T.Y., S.S.), Graduate School of Medicine, Kyoto University, Kyoto, and Department of Pediatrics (S.A.), Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Correspondence to Koji Hasegawa, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. E-mail koj{at}kuhp.kyoto-u.ac.jp
Abstract
Abstract—Endothelin-1 (ET-1) acts not only as a growth-promoting peptide but also as a potent survival factor against myocardial cell apoptosis. However, the signaling pathways 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 hydrogen peroxide–induced increase in the percentage of TdT-mediated dUTP-biotin nick-end labeling–positive myocytes. Apoptosis inhibition by ET-1 was confirmed by cytofluorometric analysis as well as by examination of the ladder formation, morphological features, and caspase-3 cleavage. We have found that ET-1 converts the nuclear factor of activated T lymphocytes (NFATc) in cardiac myocytes into high-mobility forms and translocates cytoplasmic NFATc to the nuclei. In addition, ET-1 stimulates the interaction between NFATc and the cardiac-restricted zinc-finger protein GATA4 in these cells. The immunosuppressants cyclosporin A and FK506, which antagonize calcineurin, negated the inhibitory effect of ET-1 on apoptosis. Calcineurin activation de novo was sufficient to inhibit hydrogen peroxide–induced apoptosis. ET-1 induced the expression of an antiapoptotic protein bcl-2 in cardiac myocytes in a cyclosporin A–dependent manner, but it did not alter the expression of bax. Cyclosporin A also attenuated the ET-1–stimulated transcription of the bcl-2 gene in these cells. These findings demonstrate that the calcineurin pathway is required for the inhibitory effect of ET-1 on oxidant stress–induced apoptosis in cardiac myocytes.
Key Words: apoptosis • endothelin-1 • cardiac myocyte • calcineurin
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