CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo

Robert Passier, Hong Zeng, Norbert Frey, Francisco J. Naya, Rebekka L. Nicol, Timothy A. McKinsey, Paul Overbeek, James A. Richardson, Stephen R. Grant, Eric N. Olson

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392 Scopus citations

Abstract

Hypertrophic growth is an adaptive response of the heart to diverse pathological stimuli and is characterized by cardiomyocyte enlargement, sarcomere assembly, and activation of a fetal program of cardiac gene expression. A variety of Ca2+-dependent signal transduction pathways have been implicated in cardiac hypertrophy, but whether these pathways are independent or interdependent and whether there is specificity among them are unclear. Previously, we showed that activation of the Ca2+/calmodulin- dependent protein phosphatase calcineurin or its target transcription factor NFAT3 was sufficient to evoke myocardial hypertrophy in vivo. Here, we show that activated Ca2+/calmodulin-dependent protein kinases-I and -IV (CaMKI and CaMKIV) also induce hypertrophic responses in cardiomyocytes in vitro and that CaMKIV overexpressing mice develop cardiac hypertrophy with increased left ventricular end-diastolic diameter and decreased fractional shortening. Crossing this transgenic line with mice expressing a constitutively activated form of NFAT3 revealed synergy between these signaling pathways. We further show that CaMKIV activates the transcription factor MEF2 through a posttranslational mechanism in the hypertrophic heart in vivo. Activated calcineurin is a less efficient activator of MEF2-dependent transcription, suggesting that the calcineurin/NFAT and CaMK/MEF2 pathways act in parallel. These findings identify MEF2 as a downstream target for CaMK signaling in the hypertrophic heart and suggest that the CaMK and calcineurin pathways preferentially target different transcription factors to induce cardiac hypertrophy.

Original languageEnglish (US)
Pages (from-to)1395-1406
Number of pages12
JournalJournal of Clinical Investigation
Volume105
Issue number10
DOIs
StatePublished - May 2000

ASJC Scopus subject areas

  • Medicine(all)

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    Passier, R., Zeng, H., Frey, N., Naya, F. J., Nicol, R. L., McKinsey, T. A., Overbeek, P., Richardson, J. A., Grant, S. R., & Olson, E. N. (2000). CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo. Journal of Clinical Investigation, 105(10), 1395-1406. https://doi.org/10.1172/JCI8551