[HTML][HTML] A calcineurin-dependent transcriptional pathway for cardiac hypertrophy

JD Molkentin, JR Lu, CL Antos, B Markham… - Cell, 1998 - cell.com
JD Molkentin, JR Lu, CL Antos, B Markham, J Richardson, J Robbins, SR Grant, EN Olson
Cell, 1998cell.com
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 hypertrophy is induced by the calcium-dependent
phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling
it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription
factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that …
Abstract
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 hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of calcineurin activity blocks hypertrophy in vivo and in vitro. These results define a novel hypertrophic signaling pathway and suggest pharmacologic approaches to prevent cardiac hypertrophy and heart failure.
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