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(Circulation. 2008;118:1567-1576.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Conditional Dicer Gene Deletion in the Postnatal Myocardium Provokes Spontaneous Cardiac Remodeling

Paula A. da Costa Martins, PhD; Meriem Bourajjaj, PhD; Monika Gladka, MSc; Mara Kortland, MSc; Ralph J. van Oort, PhD; Yigal M. Pinto, MD, PhD; Jeffery D. Molkentin, PhD; Leon J. De Windt, PhD

From the Hubrecht Institute and Interuniversity Cardiology Institute Netherlands, Royal Netherlands Academy of Sciences, Utrecht, Netherlands (P.A.d.C.M., M.B., M.G., M.K., R.J.v.O., L.J.D.W.); Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands (P.A.d.C.M., M.B., M.G., L.J.D.W.); Heart Failure Research Center, Academic Medical Center, Amsterdam, Netherlands (Y.M.P.); and Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio (J.D.M.).

Correspondence to Dr Leon J. De Windt, Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands. E-mail l.j.dewindt{at}umcutrecht.nl

Received January 29, 2008; accepted July 15, 2008.

Background— Dicer, an RNAse III endonuclease critical for processing of pre-microRNAs (miRNAs) into mature 22-nucleotide miRNAs, has proven a useful target to dissect the significance of miRNAs biogenesis in mammalian biology.

Methods and Results— To circumvent the embryonic lethality associated with germline null mutations for Dicer, we triggered conditional Dicer loss through the use of a tamoxifen-inducible Cre recombinase in the postnatal murine myocardium. Targeted Dicer deletion in 3-week-old mice provoked premature death within 1 week accompanied by mild ventricular remodeling and dramatic atrial enlargement. In the adult myocardium, loss of Dicer induced rapid and dramatic biventricular enlargement, accompanied by myocyte hypertrophy, myofiber disarray, ventricular fibrosis, and strong induction of fetal gene transcripts. Comparative miRNA profiling revealed a set of miRNAs that imply causality between miRNA depletion and spontaneous cardiac remodeling.

Conclusions— Overall, these results indicate that modifications in miRNA biogenesis affect both juvenile and adult myocardial morphology and function.

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Clinical Summaries
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