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(Circulation Research. 2009;105:585.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure

Prakash K. Rao, Yumiko Toyama, H. Rosaria Chiang, Sumeet Gupta, Michael Bauer, Rostislav Medvid, Ferenc Reinhardt, Ronglih Liao, Monty Krieger, Rudolf Jaenisch, Harvey F. Lodish, Robert Blelloch

From the Whitehead Institute for Biomedical Research (P.K.R., H.R.C., S.G., F.R., R.J., H.F.L.) and the Department of Biology (Y.T., M.K., R.J., H.F.L.), Massachusetts Institute of Technology, Cambridge; the Division of Cardiology (M.B., R.L.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and the Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Biology, Department of Urology (R.M., R.B.), University of California, San Francisco.

Correspondence to Harvey F. Lodish, PhD, Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142. E-mail lodish{at}wi.mit.edu and Robert Blelloch, MD, PhD, The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, and Department of Urology, University of California, San Francisco, San Francisco, CA. E-mail blellochr@stemcell.ucsf.edu

Rationale: Heart failure is a deadly and devastating disease that places immense costs on an aging society. To develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function.

Objective: microRNAs are important regulators of gene expression, and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity.

Methods and Results: First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Second, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8, a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality.

Conclusions: These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs may ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8.

Key Words: cardiac disease • cardiac failure • cardiomyocytes • myocardium • microRNA

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