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Molecular and Cellular Biology, April 2009, p. 2193-2204, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01222-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

MicroRNA-1 Negatively Regulates Expression of the Hypertrophy-Associated Calmodulin and Mef2a Genes{triangledown} ,{dagger}

Sadakatsu Ikeda,1,{ddagger} Aibin He,1,{ddagger} Sek Won Kong,1 Jun Lu,2 Rafael Bejar,3 Natalya Bodyak,4 Kyu-Ho Lee,1,§ Qing Ma,1 Peter M. Kang,4 Todd R. Golub,2,5 and William T. Pu1,6*

Department of Cardiology, Children's Hospital Boston, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115,1 Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, the Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, and Harvard Medical School, Boston, Massachusetts 02115,2 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115,3 Cardiovascular Division, Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Massachusetts 02115,4 Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, and Howard Hughes Medical Institute, Chevy Chase, Maryland 20815,5 Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts 021386

Received 4 August 2008/ Returned for modification 1 October 2008/ Accepted 27 January 2009

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.

* Corresponding author. Mailing address: Enders 1254, Children's Hospital Boston, 300 Longwood Ave., Boston, MA 02115. Phone: (617) 327-2903. Fax: (617) 730-0140. E-mail: wpu{at}enders.tch.harvard.edu

{triangledown} Published ahead of print on 2 February 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} S.I. and A.H. contributed equally to this work.

§ Present address: Medical University of South Carolina, BSB-601, 173 Ashley Avenue, Charleston, SC 29445.

Molecular and Cellular Biology, April 2009, p. 2193-2204, Vol. 29, No. 8
0270-7306/09/$08.00+0     doi:10.1128/MCB.01222-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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