NFATc4 is negatively regulated in miR-133a-mediated cardiomyocyte hypertrophic repression.
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.
Li
Qi
Q
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.
Lin
Xi
X
Yang
Xiangsheng
X
Chang
Jiang
J
D020413:3' Untranslated Regions / Q000235:genetics; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015153:Blotting, Western; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D019295:Computational Biology; D005822:Genetic Vectors; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000648:ultrastructure; D050778:NFATC Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics*; D010957:Plasmids / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D020413:3' Untranslated Regions; C549446:MIRN133 microRNA, rat; D035683:MicroRNAs; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C477593:Nfatc4 protein, rat; D012333:RNA, Messenger; D008156:Luciferases