Targeting calcineurin and associated pathways in cardiac hypertrophy and failure

Cardiac hypertrophy occurs in response to long-term increases in haemodynamic load related to a variety of physiological and pathological conditions. Cardiac hypertrophy developing in pathological conditions with increased load often progresses to a decompensated stage with cardiac contractile dysfunction, clinical signs of heart failure and premature death. Cardiac hypertrophy associated with adverse outcomes is said to be maladaptive. Conversely, there are settings where cardiac hypertrophy appears to be purely adaptive (e.g., hypertrophy in response to regular physical exercise). In these circumstances, hypertrophy is associated with preserved contractile performance and a favourable prognosis. Cardiac myocyte hypertrophy is controlled by growth factor receptors and mechanical stress sensors which activate a complex network of signalling pathways. These pathways promote a multitude of qualitative and quantitative changes in gene expression levels in cardiomyocytes. Reprogramming of gene expression, much more than cardiac (myocyte) hypertrophy per se, ultimately determines if cardiac hypertrophy will be adaptive or maladaptive. Pharmacological modification of gene expression in the hypertrophied heart may, therefore, be an attractive approach to prevent or even treat maladaptive hypertrophy and heart failure. Calcineurin is a serine-threonine phosphatase that is activated by sustained increases in [Ca2+]i in cardiomyocytes. Although it has been firmly established that calcineurin plays a critical role in the development of cardiac hypertrophy, the question of whether calcineurin activation serves an adaptive or maladaptive role is still unresolved. An answer to this question is crucial if calcineurin is to be developed as a drug target. The authors propose that calcineurin acts as a double-edged sword; excessive activation of calcineurin is maladaptive, its activation at endogenous levels and at specific subcellular microdomains, however, promotes adaptation. Calcineurin itself may, therefore, not be a convenient target for drug development. However, because maladaptive hypertrophy is ultimately a transcriptional disorder, definition of the transcriptional programme activated by distinct calcineurin activation levels may permit identification of novel, attractive drug targets.