A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.
Journal:
Cell 1998 AprAuthors:
Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, Olson EN
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 transc
...[more]ription. 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.[less]
Mesh Headings:
Angiotensin II, Animals, Animals, Newborn, Atrial Natriuretic Factor, Calcineurin, Cardiomegaly, Cell Nucleus, DNA-Binding Proteins, GATA4 Transcription Factor, Immunosuppressive Agents, Mice, Mice, Transgenic, Myocardium, NFATC Transcription Factors, Natriuretic Peptide, Brain, Nuclear Proteins, Phenylephrine, Promoter Regions, Genetic, Rats, Recombinant Fusion Proteins, Signal Transduction, Transcription Factors, Transcription, Genetic, Transcriptional Activation, Zinc Fingers