Cardiac cell hypertrophy in vitro: role of calcineurin/NFAT as Ca2+ signal integrators.

Various conditions were used to investigate the importance of Ca2+ signaling in triggering hypertrophy in neonatal rat cardiomyocytes in vitro. An increase in cell size and sarcomere reorganization were induced not only by treatment with receptor agonists, such as angiotensin II, aldosterone, and norepinephrine, but also by a small depolarization caused by an increase in the KCl concentration of the medium. This latter treatment has no direct effects on receptor signaling. All these hypertrophic treatments caused a long-lasting increase in the frequency of spontaneous [Ca2+] oscillations, causing nuclear translocation of transfected NFAT (GFP). Cyclosporine A inhibited hypertrophy and NFAT translocation, but not the increased oscillation frequency. We propose here that calcineurin-NFAT can act as integrators of the Ca2+ signal and can decode alterations in the frequency even of very rapid Ca2+ oscillations.