Published online before print November 13, 2003, doi: 10.1161/01.RES.0000107197.99679.77
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 28, 2003
Revised on November 3, 2003
Accepted on November 6, 2003
Calcineurin A
Gene Targeting Predisposes the Myocardium to Acute Ischemia-Induced Apoptosis and Dysfunction
Orlando F. Bueno ;
From the Department of Pediatrics, Division of Molecular Cardiovascular Biology (O.F.B., R.A.K., B.J.W., Y.-S.D., R.K., T.E.H., J.D.M.), Children’s Hospital Medical Center, Ohio; Department of Cardiology (D.J.L., P.A.D.), Cardiovascular Research Institute Maastricht, University Hospital Maastricht, the Netherlands, and Department of Cardiology, Heart, Lung Center Utrecht, Utrecht, the Netherlands; Department of Pediatrics, Division of Cardiovascular Imaging (B.J.G., T.R.K.), Children’s Hospital Medical Center, Ohio; and the Department of Pediatrics, Division of Pediatric Informatics (B.J.A.), Children’s Hospital Medical Center, Ohio.
* To whom correspondence should be addressed. E-mail: jeff.molkentin{at}cchmc.org.
Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart. Calcineurin A
gene-targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly, calcineurin A-/- hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in calcineurin A-/- hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.
Key words: signaling • calcineurin • apoptosis • heart failure • transcription
This article has been cited by other articles:
 |
|
 |
|
  J. R. Somers, P. L. Beck, J. P. Lees-Miller, D. Roach, Y. Li, J. Guo, S. Loken, S. Zhan, L. Semeniuk, and H. J. Duff iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1122 - H1131. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Piot, P. Croisille, P. Staat, H. Thibault, G. Rioufol, N. Mewton, R. Elbelghiti, T. T. Cung, E. Bonnefoy, D. Angoulvant, et al. Effect of Cyclosporine on Reperfusion Injury in Acute Myocardial Infarction N. Engl. J. Med., July 31, 2008; 359(5): 473 - 481. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Porta, S. A. Serra, M. Huch, M. A. Valverde, F. Llorens, X. Estivill, M. L. Arbones, and E. Marti RCAN1 (DSCR1) increases neuronal susceptibility to oxidative stress: a potential pathogenic process in neurodegeneration Hum. Mol. Genet., May 1, 2007; 16(9): 1039 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Parsons, D. P. Millay, M. A. Sargent, F. J. Naya, E. M. McNally, H. L. Sweeney, and J. D. Molkentin Genetic Disruption of Calcineurin Improves Skeletal Muscle Pathology and Cardiac Disease in a Mouse Model of Limb-Girdle Muscular Dystrophy J. Biol. Chem., March 30, 2007; 282(13): 10068 - 10078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nieves-Cintron, G. C. Amberg, C. B. Nichols, J. D. Molkentin, and L. F. Santana Activation of NFATc3 Down-regulates the beta1 Subunit of Large Conductance, Calcium-activated K+ Channels in Arterial Smooth Muscle and Contributes to Hypertension J. Biol. Chem., February 2, 2007; 282(5): 3231 - 3240. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Suzuki, E. Bayna, H. L. Li, E. D. Molle, and W. Y.W. Lew Lipopolysaccharide Activates Calcineurin in Ventricular Myocytes J. Am. Coll. Cardiol., January 30, 2007; 49(4): 491 - 499. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Obasanjo-Blackshire, R. Mesquita, R. I. Jabr, J. D. Molkentin, S. L. Hart, M. S. Marber, Y. Xia, and R. J. Heads Calcineurin regulates NFAT-dependent iNOS expression and protection of cardiomyocytes: Co-operation with Src tyrosine kinase Cardiovasc Res, September 1, 2006; 71(4): 672 - 683. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Liu, B. J. Wilkins, Y. J. Lee, H. Ichijo, and J. D. Molkentin Direct Interaction and Reciprocal Regulation between ASK1 and Calcineurin-NFAT Control Cardiomyocyte Death and Growth Mol. Cell. Biol., May 15, 2006; 26(10): 3785 - 3797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sanna, E. B. Brandt, R. A. Kaiser, P. Pfluger, S. A. Witt, T. R. Kimball, E. van Rooij, L. J. De Windt, M. E. Rothenberg, M. H. Tschop, et al. Modulatory calcineurin-interacting proteins 1 and 2 function as calcineurin facilitators in vivo PNAS, May 9, 2006; 103(19): 7327 - 7332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Lee, S. Dahi, R. Mahimkar, N. L. Tulloch, M. A. Alfonso-Jaume, D. H. Lovett, and R. Sarkar Intronic regulation of matrix metalloproteinase-2 revealed by in vivo transcriptional analysis in ischemia PNAS, November 8, 2005; 102(45): 16345 - 16350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mathew, E. Mascareno, and M. A. Q. Siddiqui A Ternary Complex of Transcription Factors, Nished and NFATc4, and Co-activator p300 Bound to an Intronic Sequence, Intronic Regulatory Element, Is Pivotal for the Up-regulation of Myosin Light Chain-2v Gene in Cardiac Hypertrophy J. Biol. Chem., September 24, 2004; 279(39): 41018 - 41027. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Fiedler and K. C Wollert Interference of antihypertrophic molecules and signaling pathways with the Ca2+-calcineurin-NFAT cascade in cardiac myocytes Cardiovasc Res, August 15, 2004; 63(3): 450 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D Molkentin Calcineurin-NFAT signaling regulates the cardiac hypertrophic response in coordination with the MAPKs Cardiovasc Res, August 15, 2004; 63(3): 467 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. P.M van Empel and L. J De Windt Myocyte hypertrophy and apoptosis: a balancing act Cardiovasc Res, August 15, 2004; 63(3): 487 - 499. [Abstract] [Full Text] [PDF]
|
|