A CALCINEURIN-DEPENDENT TRANSCRIPTIONAL PATHWAY FOR CARDIAC-HYPERTROPHY

In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. We show that cardiac hypertrop hy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to trans locate to the nucleus. NF-AT3 interacts with the cardiac zinc finger t ranscription factor GATA4, resulting in synergistic activation of card iac transcription. Transgenic mice that express activated forms of cal cineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of ca lcineurin activity blocks hypertrophy in vivo and in vitro. These resu lts define a novel hypertrophic signaling pathway and suggest pharmaco logic approaches to prevent cardiac hypertrophy and heart failure.