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A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.

Cell | Apr 17, 1998

http://www.ncbi.nlm.nih.gov/pubmed/9568714

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.

Pubmed ID: 9568714 RIS Download

Mesh terms: 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

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Associated grants

  • Agency: NHLBI NIH HHS, Id: R01 HL053351

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