A calcineurin-dependent transcriptional pathway for cardiac hypertrophy

Jeffery D. Molkentin, Jian Rong Lu, Christopher L. Antos, Bruce Markham, James Richardson, Jeffrey Robbins, Stephen R. Grant, Eric N. Olson

Research output: Contribution to journalArticle

2031 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)215-228
Number of pages14
JournalCell
Volume93
Issue number2
DOIs
StatePublished - Apr 17 1998

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Calcineurin
Cardiomegaly
Heart Failure
GATA4 Transcription Factor
Chemical activation
Zinc Fingers
Transcription
Cell Size
Hypertrophy
Transgenic Mice
Transcriptional Activation
Zinc
Heart Diseases
Myocardium
Transcription Factors
Genes
Calcium

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. / Molkentin, Jeffery D.; Lu, Jian Rong; Antos, Christopher L.; Markham, Bruce; Richardson, James; Robbins, Jeffrey; Grant, Stephen R.; Olson, Eric N.

In: Cell, Vol. 93, No. 2, 17.04.1998, p. 215-228.

Research output: Contribution to journalArticle

Molkentin, JD, Lu, JR, Antos, CL, Markham, B, Richardson, J, Robbins, J, Grant, SR & Olson, EN 1998, 'A calcineurin-dependent transcriptional pathway for cardiac hypertrophy', Cell, vol. 93, no. 2, pp. 215-228. https://doi.org/10.1016/S0092-8674(00)81573-1
Molkentin JD, Lu JR, Antos CL, Markham B, Richardson J, Robbins J et al. A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell. 1998 Apr 17;93(2):215-228. https://doi.org/10.1016/S0092-8674(00)81573-1
Molkentin, Jeffery D. ; Lu, Jian Rong ; Antos, Christopher L. ; Markham, Bruce ; Richardson, James ; Robbins, Jeffrey ; Grant, Stephen R. ; Olson, Eric N. / A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. In: Cell. 1998 ; Vol. 93, No. 2. pp. 215-228.
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