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

2067 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Molkentin, J. D., Lu, J. R., Antos, C. L., Markham, B., Richardson, J., Robbins, J., Grant, S. R., & Olson, E. N. (1998). A calcineurin-dependent transcriptional pathway for cardiac hypertrophy. Cell, 93(2), 215-228. https://doi.org/10.1016/S0092-8674(00)81573-1