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Am J Physiol Heart Circ Physiol. 2010 May;298(5):H1340-7. doi: 10.1152/ajpheart.00592.2009. Epub 2010 Feb 19.

NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression.

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1
Center for Molecular Development and Disease, Institute of Biosciences and Technology, Texas A&M Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030, USA.

Abstract

Activation of NFAT (nuclear factor of activated T cells)-mediated hypertrophic signaling is a major regulatory response to hypertrophic stimuli. A recent study unveiled potential regulatory roles for microRNA-133a (miR-133a) in cardiac hypertrophy. To date, however, no connection has been made between miR-133a and NFAT signaling. In this study, we determined that NFATc4, a hypertrophy-associated mediator, is negatively regulated by miR-133a. Two conserved base-pairing sites between the NFATc4 3'-untranslated region (UTR) and miR-133a were verified. Mutation of these sites in the NFATc4 3'-UTR completely blocked the negative effect of miR-133a on NFATc4, suggesting that NFATc4 is a direct target for miR-133a regulation. Using a gain-of-function approach, we demonstrate that miR-133 significantly reduces the endogenous level of, as well as the hypertrophic stimulus-mediated increase in, NFATc4 gene expression. This latter effect of miR-133a on NFATc4 gene expression was coincided with an attenuated cardiomyocyte hypertrophy induced by an alpha-adrenergic receptor agonist. Conversely, cells treated with miR-133a inhibitor resulted in an increase in NFATc4 expression level. Application of miR-133a had no apparent effect on NFATc4 nuclear localization. We conclude that the negative regulation of NFATc4 expression contributes to miR-133a-mediated hypertrophic repression.

PMID:
20173049
PMCID:
PMC3774484
DOI:
10.1152/ajpheart.00592.2009
[Indexed for MEDLINE]
Free PMC Article
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