Calcineurin plays a critical role in pressure overload-induced cardiac hypertrophy

Background-Cardiac hypertrophy is a fundamental adaptive response to hemody namic overload; how mechanical load induces cardiac hypertrophy, however, r emains elusive. It was recently reported that activation of a calcium-depen dent phosphatase, calcineurin, induces cardiac hypertrophy. In the present study, we examined whether calcineurin plays a critical role in pressure ov erload-induced cardiac hypertrophy. Methods and Results-Pressure overload produced by constriction of the abdom inal aorta increased the activity of calcineurin in the rat heart and induc ed cardiac hypertrophy, including reprogramming of gene expression. Treatme nt of rats with a calcineurin inhibitor, FK506, inhibited the activation of calcineurin and prevented the pressure overload-induced cardiac hypertroph y and fibrosis without change of hemodynamic parameters. Load-induced expre ssion of immediate-early-response genes and fetal genes was also suppressed by the FK506 treatment. Conclusions-The present results suggest that the calcineurin signaling path way plays a pivotal role in load-induced cardiac hypertrophy and may pave t he way for a novel pharmacological approach to prevent cardiac hypertrophy.