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 Abeta 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 Abeta-/- 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 Abeta-/- 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.