Calcineurin inhibitor attenuates the development and induces the regression of cardiac hypertrophy in rats with salt-sensitive hypertension

Background-It remains unclear how hemodynamic overload induces cardiac hype rtrophy. Recently, activation of calcium-dependent phosphatase, calcineurin , has been elucidated to induce cardiac hypertrophy. In the present study, we examined the role of calcineurin in load-induced cardiac hypertrophy by using Dahl salt-sensitive (DS) rats, which develop both pressure and volume overload when fed a high salt diet. Methods and Results-In the DS rat heart, the activity of calcineurin was in creased and cardiac hypertrophy was induced by high salt diet. Treatment of DS rats with the calcineurin inhibitor FK506 (0.1 or 0.01 mg/kg twice dail y) from the age of 6 weeks to 12 weeks inhibited the activation of calcineu rin in the heart in a dose-dependent manner and attenuated the development of load-induced cardiac hypertrophy and fibrosis without change of hemodyna mic parameters. Additionally, treatment with 0.1 mg/kg twice daily but not with 0.01 mg/kg twice daily of FK506 from the age of 12 weeks to 16 weeks i nduced regression of cardiac hypertrophy in DS rats. Load-induced reprogram ming of gene expression was also suppressed by the FK506 treatment. Conclusions-These results suggest that calcineurin is involved in the devel opment of cardiac hypertrophy in rats with salt-sensitive hypertension and that inhibition of calcineurin could induce regression of cardiac hypertrop hy.