© 2000 American Heart Association, Inc.
Integrative Physiology |
Calcineurin-Mediated Hypertrophy Protects Cardiomyocytes From Apoptosis In Vitro and In Vivo
An Apoptosis-Independent Model of Dilated Heart Failure
From the Departments of Pediatrics (L.J.D.W., H.W.L., T.T., J.D.M.) and Cardiology (G.W.D.), University of Cincinnati, and Division of Molecular Cardiovascular Biology (L.J.D.W., H.W.L., T.T., J.D.M.), Children’s Hospital Medical Center, Cincinnati, Ohio; Departments of Medicine and Cell Biology (D.W., R.N.K.), Albert Einstein College of Medicine, The Bronx, NY; and Kimmel Cancer Center and Department of Microbiology and Immunology (G.C.), Thomas Jefferson University, Philadelphia, Pa.
Correspondence to Jeffery D. Molkentin, Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail molkj0{at}chmcc.org
Abstract—We have previously shown
that the calcium-calmodulin–regulated phosphatase
calcineurin (PP2B) is sufficient to induce cardiac
hypertrophy that transitions to heart failure in transgenic
mice. Given the rapid onset of heart failure in these mice, we
hypothesized that calcineurin signaling would stimulate myocardial cell
apoptosis. However, utilizing multiple approaches, we
determined that calcineurin-mediated hypertrophy protected
cardiac myocytes from apoptosis, suggesting a model of heart
failure that is independent of apoptosis. Adenovirally mediated
gene transfer of a constitutively active calcineurin cDNA (AdCnA) was
performed in cultured neonatal rat cardiomyocytes to
elucidate the mechanism whereby calcineurin affected myocardial cell
viability. AdCnA infection, which induced myocyte
hypertrophy and atrial natriuretic factor
expression, protected against apoptosis induced by
2-deoxyglucose or staurosporine, as assessed by terminal
deoxynucleotidyltransferase-mediated
dUTP nick end labeling (TUNEL) labeling, caspase-3 activation, DNA
laddering, and cellular morphology. The level of protection conferred
by AdCnA was similar to that of adenoviral Bcl-xL gene
transfer or hypertrophy induced by
phenylephrine. In vivo, failing hearts from
calcineurin-transgenic mice did not demonstrate increased TUNEL
labeling and, in fact, demonstrated a resistance to
ischemia/reperfusion–induced apoptosis. We determined
that the mechanism whereby calcineurin afforded protection from
apoptosis was partially mediated by nuclear factor of activated
T cells (NFAT3) signaling and partially by Akt/protein kinase B (PKB)
signaling. Although calcineurin activation protected myocytes
from apoptosis, inhibition of calcineurin with
cyclosporine was not sufficient to induce TUNEL labeling in
Gq
-transgenic mice or in cultured cardiomyocytes.
Collectively, these data identify a calcineurin-dependent mouse model
of dilated heart failure that is independent of apoptosis.
Key Words: calcineurin • apoptosis • cardiac hypertrophy • phenylephrine • caspase-3
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J. N. Muth, I. Bodi, W. Lewis, G. Varadi, and A. Schwartz A Ca2+-Dependent Transgenic Model of Cardiac Hypertrophy : A Role for Protein Kinase C{{alpha}} Circulation, January 2, 2001; 103(1): 140 - 147. [Abstract] [Full Text] [PDF]
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S. F. Steinberg The Cellular Actions of {beta}-Adrenergic Receptor Agonists : Looking Beyond cAMP Circ. Res., December 8, 2000; 87(12): 1079 - 1082. [Full Text] [PDF]
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J. D. Molkentin Calcineurin and Beyond : Cardiac Hypertrophic Signaling Circ. Res., October 27, 2000; 87(9): 731 - 738. [Abstract] [Full Text] [PDF]
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P. M. Kang and S. Izumo Apoptosis and Heart Failure : A Critical Review of the Literature Circ. Res., June 9, 2000; 86(11): 1107 - 1113. [Full Text] [PDF]
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L. J. De Windt, H. W. Lim, S. Haq, T. Force, and J. D. Molkentin Calcineurin Promotes Protein Kinase C and c-Jun NH2-terminal Kinase Activation in the Heart. CROSS-TALK BETWEEN CARDIAC HYPERTROPHIC SIGNALING PATHWAYS J. Biol. Chem., April 28, 2000; 275(18): 13571 - 13579. [Abstract] [Full Text] [PDF]
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S. Saito, Y. Hiroi, Y. Zou, R. Aikawa, H. Toko, F. Shibasaki, Y. Yazaki, R. Nagai, and I. Komuro beta -Adrenergic Pathway Induces Apoptosis through Calcineurin Activation in Cardiac Myocytes J. Biol. Chem., October 27, 2000; 275(44): 34528 - 34533. [Abstract] [Full Text] [PDF]
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H. W. Lim, L. New, J. Han, and J. D. Molkentin Calcineurin Enhances MAPK Phosphatase-1 Expression and p38 MAPK Inactivation in Cardiac Myocytes J. Biol. Chem., May 4, 2001; 276(19): 15913 - 15919. [Abstract] [Full Text] [PDF]
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C. L. Antos, T. A. McKinsey, N. Frey, W. Kutschke, J. McAnally, J. M. Shelton, J. A. Richardson, J. A. Hill, and E. N. Olson Activated glycogen synthase-3beta suppresses cardiac hypertrophy in vivo PNAS, January 22, 2002; 99(2): 907 - 912. [Abstract] [Full Text] [PDF]
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T. Kakita, K. Hasegawa, E. Iwai-Kanai, S. Adachi, T. Morimoto, H. Wada, T. Kawamura, T. Yanazume, and S. Sasayama Calcineurin Pathway Is Required for Endothelin-1-Mediated Protection Against Oxidant Stress-Induced Apoptosis in Cardiac Myocytes Circ. Res., June 22, 2001; 88(12): 1239 - 1246. [Abstract] [Full Text] [PDF]
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