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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 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

Authors

  • Molkentin JD
  • Lu JR
  • Antos CL
  • Markham B
  • Richardson J
  • Robbins J
  • Grant SR
  • Olson EN

Journal

Cell

Publication Data

April 17, 1998

Associated Grants

  • Agency: NHLBI NIH HHS, Id: R01 HL053351

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