Circulation Research. 2003
Published online before print March 27, 2003, doi: 10.1161/01.RES.0000069211.82346.46
Published online before print March 27, 2003, doi: 10.1161/01.RES.0000069211.82346.46
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Submitted on October 28, 2002
Revised on February 27, 2003
Accepted on March 18, 2003
NFAT Transcription Factors Are Critical Survival Factors That Inhibit Cardiomyocyte Apoptosis During Phenylephrine Stimulation In Vitro
William T. Pu ;
From the Department of Cardiology (W.T.P.), Children's Hospital, Boston, Mass; and Division of Cardiovascular Research (Q.M., S.I.), Beth Israel Deaconess Medical Center, Boston, Mass.
* To whom correspondence should be addressed. E-mail: sizumo{at}caregroup.harvard.edu.
Biomechanical stress on the heart results in activation of numerous signaling cascades, leading to cardiomyocyte hypertrophy, apoptosis, and ultimately, heart failure. The Ca2+-dependent phosphatase calcineurin is an essential mediator of cardiac hypertrophy, and in most but not all studies, calcineurin inhibition attenuated cardiac hypertrophy in vivo. However, calcineurin inhibition has been reported to have adverse effects on cardiac remodeling and cardiomyocyte apoptosis. Calcineurin regulates the activity of a number of downstream targets, including the transcription factors NFAT, MEF2, and NF-
B, and the apoptotic factor Bad. To evaluate the contribution of NFAT activation by calcineurin to cardiomyocyte responses to hypertrophic stimulation, we used adenovirus to express VIVIT, a selective peptide inhibitor of calcineurin-mediated NFAT activation. We found that selective NFAT inhibition during phenylephrine stimulation inhibited hypertrophy but resulted in increased cardiomyocyte apoptosis. In contrast, nonselective inhibition of calcineurin by cyclosporin A did not cause cardiomyocyte apoptosis after phenylephrine stimulation. Cyclosporin A suppressed the effect of VIVIT on cardiomyocyte apoptosis. These results demonstrate that during phenylephrine stimulation calcineurin activates both pro- and antiapoptotic pathways in cardiomyocytes, and that NFAT activity is a critical component of the antiapoptotic pathway that regulates whether the outcome of calcineurin activation is cardiomyocyte apoptosis or survival.
Key words: apoptosis • cardiac hypertrophy • calcineurin • NFAT • phenylephrine
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