A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy

Cell. 1998 Apr 17;93(2):215-28. doi: 10.1016/s0092-8674(00)81573-1.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiotensin II / pharmacology
  • Animals
  • Animals, Newborn
  • Atrial Natriuretic Factor / genetics
  • Calcineurin / genetics
  • Calcineurin / physiology*
  • Cardiomegaly / enzymology
  • Cardiomegaly / genetics*
  • Cardiomegaly / prevention & control
  • Cell Nucleus / metabolism
  • DNA-Binding Proteins / metabolism
  • GATA4 Transcription Factor
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Mice, Transgenic
  • Myocardium / metabolism
  • Myocardium / pathology*
  • NFATC Transcription Factors
  • Natriuretic Peptide, Brain
  • Nuclear Proteins*
  • Phenylephrine / pharmacology
  • Promoter Regions, Genetic / genetics
  • Rats
  • Recombinant Fusion Proteins
  • Signal Transduction / physiology*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transcriptional Activation / physiology*
  • Zinc Fingers

Substances

  • DNA-Binding Proteins
  • GATA4 Transcription Factor
  • Immunosuppressive Agents
  • NFATC Transcription Factors
  • NFATC4 protein, human
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • Transcription Factors
  • Angiotensin II
  • Natriuretic Peptide, Brain
  • Phenylephrine
  • Atrial Natriuretic Factor
  • Calcineurin