MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes.
Calcium signaling is a central regulator of cardiomyocyte growth and function. Calmodulin is a critical mediator of calcium signals. Because the amount of calmodulin within cardiomyocytes is limiting, the precise control of calmodulin expression is important for the regulation of calcium signaling. In this study, we show for the first time that calmodulin levels are regulated posttranscriptionally in heart failure. The cardiomyocyte-restricted microRNA miR-1 inhibited the translation of calmodulin-encoding mRNAs via highly conserved target sites within their 3' untranslated regions. In keeping with its effect on calmodulin expression, miR-1 downregulated calcium-calmodulin signaling through calcineurin to NFAT. miR-1 also negatively regulated the expression of Mef2a and Gata4, key transcription factors that mediate calcium-dependent changes in gene expression. Consistent with the downregulation of these hypertrophy-associated genes, miR-1 attenuated cardiomyocyte hypertrophy in cultured neonatal rat cardiomyocytes and in the intact adult heart. Our data indicate that miR-1 regulates cardiomyocyte growth responses by negatively regulating the calcium signaling components calmodulin, Mef2a, and Gata4.
Ikeda
Sadakatsu
S
Department of Cardiology, Children's Hospital Boston, Department of Genetics, Harvard Medical School, Boston, Massachusetts 021151, USA.
He
Aibin
A
Kong
Sek Won
SW
Lu
Jun
J
Bejar
Rafael
R
Bodyak
Natalya
N
Lee
Kyu-Ho
KH
Ma
Qing
Q
Kang
Peter M
PM
Golub
Todd R
TR
Pu
William T
WT
D000818:Animals; D002147:Calmodulin; D006332:Cardiomegaly / Q000209:etiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D050991:GATA4 Transcription Factor / Q000235:genetics*; D005786:Gene Expression Regulation; D006333:Heart Failure; D006984:Hypertrophy; D066298:In Vitro Techniques; D064326:MEF2 Transcription Factors; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac; D018006:Myogenic Regulatory Factors / Q000235:genetics*
D002147:Calmodulin; D050991:GATA4 Transcription Factor; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D018006:Myogenic Regulatory Factors