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Received January 16, 2002
Accepted after revision March 20, 2002
1 Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH and Physician Scientist Training Program, Molecular and Developmental Biology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH, USA
2 Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA
* To whom correspondence should be addressed. E-mail: molkj0{at}chmcc.org.
The heart is a dynamic organ capable of adapting its size and architecture in response to alterations in workload associated with developmental maturation, physiological stimulation and pathological diseases. Such alterations in heart size typically result from the hypertrophic growth of individual myocytes, but not myocyte cellular proliferation. In recent years, a great deal of investigation has gone toward elucidating the molecular signalling machinery that underlies the hypertrophic response and manner in which increased cardiac load promotes alterations in gene expression. To this end, the Ca2+-calmodulin-activated phosphatase calcineurin has been proposed as a necessary component of the multi-pathway hypertrophy program in the heart. Despite initial controversy over this hypothesis due to disparate results from pharmacological inhibitory studies in animal models of hypertrophy, compelling data from genetic models with calcineurin inhibition now exist. This review will summarize many of these studies and will attempt to address a number of unanswered issues. In particular, specific downstream mediators of calcineurin signalling will be discussed, as well as the need to identify calcineurin's temporal activation profile, transcriptional targets and cross-communication with other reactive signalling pathways in the heart. Finally, we will present evidence suggesting that calcineurin, as a Ca2+-responsive enzyme, may function as an internal load sensor in cardiac myocytes, matching output demands to hypertrophic growth.
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