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(Circulation Research. 2004;94:91.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Calcineurin Aß Gene Targeting Predisposes the Myocardium to Acute Ischemia-Induced Apoptosis and Dysfunction

Orlando F. Bueno, Daniel J. Lips, Robert A. Kaiser, Benjamin J. Wilkins, Yan-Shan Dai, Betty J. Glascock, Raisa Klevitsky, Timothy E. Hewett, Thomas R. Kimball, Bruce J. Aronow, Pieter A. Doevendans, Jeffery D. Molkentin

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.

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 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 Aß 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 Aß^-/- 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 Aß^-/- 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

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