Related Experiment Videos
Calcineurin and cardiac hypertrophy: where have we been? Where are we going?
Benjamin J Wilkins1, Jeffery D Molkentin
1Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, OH, USA.
Insights
Calcineurin, a calcium-activated phosphatase, is crucial for heart hypertrophy, adapting cardiac myocytes to increased workload. Genetic studies confirm its role, highlighting its function as a load sensor in the heart.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Cellular Signaling
Background:
- The heart adapts to increased workload through myocyte hypertrophy, not proliferation.
- Understanding the molecular mechanisms of cardiac hypertrophy is critical for treating heart diseases.
Purpose of the Study:
- To review the role of calcineurin in cardiac hypertrophy.
- To discuss downstream mediators and unanswered questions regarding calcineurin signaling in the heart.
Main Methods:
- Review of genetic and pharmacological studies on calcineurin inhibition in cardiac hypertrophy models.
- Analysis of calcineurin's downstream signaling pathways and transcriptional targets.
Main Results:
- Compelling genetic evidence supports calcineurin's necessity in the cardiac hypertrophy program.
- Calcineurin acts as a calcium-responsive enzyme, potentially sensing cardiac workload.
Conclusions:
- Calcineurin is a key player in the adaptive hypertrophic growth of cardiac myocytes.
- Further research is needed to fully elucidate calcineurin's temporal activation, targets, and interactions in cardiac signaling.
Abstract:
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 Ca(2+)-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 Ca(2+)-responsive enzyme, may function as an internal load sensor in cardiac myocytes, matching output demands to hypertrophic growth.