In this hypertrophic signaling pathway, cell surface agonists or activity of cardiomyocytes, known to elevate intracellular calcium, can activate a cytoplasmically-located protein phosphatase called calcineurin. It is believed that calcineurin functions as an intracellular sensor for calcium signaling and that it transduces hypertrophic signals downstream through a recipient transcription factor known NF-AT. NF-AT is phosphorylated in the cytoplasm of cardiomyocytes, but when calcineurin is activated it becomes dephosphorylated. Upon dephosphorylation of NF-AT, this transcription factor is enabled to translocate into the nucleus where it interacts with a cardiac-restricted zinc finger transcription factor, GATA-4. This protein-protein interaction establishes a unique transcriptional code that switches on the gene regulatory program for cardiomyocyte hypertrophy and cardiac growth. In subsequent experiments they showed that activating the calcium calmodulin-dependent phosphatase calcineurin or simply dephosphorylating NF-AT is sufficient to evoke the full hypertrophic response in vivo that progresses to dilated cardiomyopathy and ultimately to sudden cardiac death. Calcineurin phosphatase can be inhibited by a family of drugs, one of which is cyclosporine A (CsA). Thus, this pathway for cardiac hypertrophy generated a great deal of interest. Olson and colleagues showed that treatment with CsA in calcineurin-transgenic mice maintained their heart size to that similar in the wild-type mice, whereas the non-treated transgenic mice developed dilated cardiomyopathy (DCM) and sudden death. CsA also prevented activation of the fetal gene program, blocks fibrosis, and prevents sudden death in the transgenic mice. The majority of mice models tested by other laboratories could be rescued from hypertrophy by CsA treatment, including models that developed hypertrophy in response to myocardial infarction (MI), salt-induced hypertension, Gq activation and sarcomeric dysfunction. Thus, a diverse array of stimuli known to elevate intracellular calcium seem to activate hypertrophy through an obligatory downstream step involving calcineurin activation. To confirm the role of calcineurin in cardiac hypertrophy, a genetic model in which calcineurin was inhibited by the muscle calcineurin inhibitory protein (MCIP), which is expressed in a muscle-specific manner with the highest expression in the heart and in skeletal muscle has been used by Olson and colleagues and other investigators. They have shown that MCIP is also sufficient to prevent hypertrophy in response to a diverse array of stimuli with no apparent consequence on the overall health or endurance of the animal. Further study revealed that MCIP is upregulated from normal hearts to hypertrophic hearts and it is also upregulated from hypertrophic to failing hearts in response to calcineurin activation and was a common response to diverse types of hypertrophic signals. The simplified model developed based on these studies for the calcineurin signaling pathway activation and regulation in cardiomyocytes is that calcium signaling activates the phosphatase, which dephosphorylates NF-AT, enabling it to translocate to the nucleus. The MCIP gene seems to be one of the most sensitive genes in cardiomyocytes to calcineurin signaling, and it has been that there are 15 tandem NF-AT binding sites in the promoter of the MCIP gene. MCIP expression causes it to feed back on calcineurin, binding directly to the catalytic subunit and diminishes calcineurin activation. It is thought that this is a built-in response by the heart to prevent further hypertrophic stimulation.

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